ADVAGRAF 1 mg PROLONGED-RELEASE HARD CAPSULES

Introduction

Package Leaflet: Information for the Patient

Advagraf 0.5mg prolonged-release hard capsules

Advagraf 1mg prolonged-release hard capsules

Advagraf 3mg prolonged-release hard capsules

Advagraf 5mg prolonged-release hard capsules

Tacrolimus

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information

1. What is Advagraf and what is it used for
2. What you need to know before you take Advagraf
3. How to take Advagraf
4. Possible side effects
5. Storage of Advagraf
6. Contents of the pack and other information

1. What is Advagraf and what is it used for

Advagraf contains the active substance tacrolimus. It is an immunosuppressant. After 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, allowing it to accept the transplanted organ.

You may also receive Advagraf to treat rejection that is occurring in your liver, kidney, heart, or other transplanted organ when any previous treatment you were following does not control this immune response after your transplant.

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 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, while Prograf is taken twice daily. This is because the capsules of Advagraf allow for prolonged release (slower release over a longer period of time) of tacrolimus. Advagraf and Prograf are not interchangeable.

Consult your doctor or pharmacist before starting to take Advagraf:

• if you are taking any other medicine (mentioned below in “Using Advagraf with other medicines”)
• if you have or have had liver problems
• if you have had diarrhea for more than one day
• if you feel strong abdominal pain accompanied by or without other symptoms such as chills, fever, nausea, or vomiting
• if you have an alteration in the electrical activity of your heart called “prolongation of the QT interval”
• if you have or have had damage to the small blood vessels, known as thrombotic microangiopathy/thrombocytopenic purpura/hemolytic uremic syndrome. Inform your doctor if you develop fever, bruising under the skin (which can appear as red spots), unexplained fatigue, confusion, yellowing of the skin or eyes, decreased urine output, loss of vision, and seizures (see section 4). When tacrolimus is taken with sirolimus or everolimus, the risk of these symptoms may increase.

Please avoid taking any herbal preparations, e.g. St. John's Wort (Hypericum perforatum) or any other plant-based product, as this may affect the effectiveness and dose of Advagraf you need to receive. If you have any doubts, please consult your doctor before taking any product or preparation based on plants.

Your doctor may need to adjust your dose of Advagraf.

You should stay in regular contact with your doctor. From time to time, to establish the correct dose of Advagraf, your doctor may need to perform blood and urine tests, heart tests, eye tests.

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

Handling precautions:

During preparation, avoid contact of any part of the body, such as skin or eyes, as well as breathing near the injection solutions, powder, or granules contained in the tacrolimus products. If such contact occurs, wash the skin and eyes.

Children and adolescents

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

Other medicines and Advagraf

Tell your doctor or pharmacist if you are using or have recently used any other medicine, including those obtained without a prescription and plant-based medicines.

Advagraf should not be used with cyclosporin (another medicine used to prevent organ transplant rejection).

If you need to visit a different doctor from your transplant specialist, tell the doctor that you are taking tacrolimus.It is possible that your doctor will need to consult with your transplant specialist if you need to use another medicine that could increase or decrease your blood level of tacrolimus.

The blood levels of Advagraf may be changed due to other medicines you are taking, and the blood levels of other medicines may be changed by the administration of Advagraf, which may require interruption, increase, or decrease of the dose of Advagraf.

Some patients have experienced increases in blood levels of tacrolimus while taking other medicines. This could cause serious side effects, such as kidney problems, nervous system problems, and heart rhythm disorders (see section 4).

The effect on blood levels of Advagraf can occur very soon after starting to use another medicine, so it may be necessary to monitor the blood level of Advagraf frequently and continuously during the first days of use of another medicine and frequently while continuing its use. Some other medicines may cause the blood levels of tacrolimus to decrease, which can increase the risk of organ transplant rejection. In particular, you should inform your doctor if you are taking or have recently taken medicines such as:

• antifungals and antibiotics, especially 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 diseases caused by CMV (human cytomegalovirus)
• HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), the booster cobicistat, and non-nucleoside reverse transcriptase inhibitors or nucleoside reverse transcriptase inhibitors for HIV (efavirenz, etravirine, nevirapine) used to treat HIV infections
• HCV protease inhibitors (e.g. telaprevir, boceprevir, the combination ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, elbasvir/grazoprevir, and glecaprevir/pibrentasvir), used to treat hepatitis C infection
• nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane (used to treat certain types of cancer)
• mycophenolic acid, used to suppress the immune system as a prevention of transplant rejection
• medicines for stomach ulcers and acid reflux (e.g. omeprazol, lansoprazol, or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
• cisapride or the antacid magnesium-aluminum hydroxide, used to treat acidity
• the contraceptive pill or other hormonal treatments with ethinylestradiol, hormonal treatments with danazol
• medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem, and verapamil)
• antiarrhythmic drugs (amiodarone) used to control arrhythmia (irregular heartbeat)
• medicines known as “statins” used to treat high cholesterol and triglycerides
• carbamazepine, phenytoin, or phenobarbital, used to treat epilepsy
• metamizole, used to treat pain and fever
• corticosteroids prednisolone or methylprednisolone, belonging to the class of corticosteroids used to treat inflammation or suppress the immune system (e.g. transplant rejection)
• nefazodone, used to treat depression
• plant-based medicines containing St. John's Wort (Hypericum perforatum) or extracts of Schisandra sphenanthera
• cannabidiol (its use includes, among others, the treatment of epileptic seizures).

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

Tell your doctor if you are taking or need to take ibuprofen (used to treat fever, inflammation, and pain), antibiotics (cotrimoxazole, vancomycin, or aminoglycoside antibiotics such as gentamicin), amphotericin B (used to treat fungal infections), or antivirals (used to treat viral infections, e.g. acyclovir, ganciclovir, cidofovir, foscarnet). These medicines may worsen kidney or nervous system problems when taken with Advagraf.

Tell your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken with sirolimus or everolimus, the risk of thrombotic microangiopathy, thrombocytopenic purpura, and hemolytic uremic syndrome may increase (see section 4).

Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, high blood pressure, and kidney disease (e.g. amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim and cotrimoxazole, which can increase potassium levels in your blood, non-steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation, and pain, anticoagulants (which prevent blood clotting), or oral medicines for the treatment of diabetes, while taking Advagraf.

If you are planning to get vaccinated, consult your doctor.

Taking Advagraf with food and drinks

Avoid grapefruit (also in juice) while you are being treated with Advagraf, as it may affect your blood levels.

Pregnancy and breastfeeding

If you are pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before taking Advagraf. A study evaluated the outcomes of pregnancy in women treated with tacrolimus and other immunosuppressants. Although this study did not provide enough evidence to draw conclusions, higher rates of spontaneous abortion were reported among liver and kidney transplant patients treated with tacrolimus, as well as higher rates of persistent hypertension, associated with protein loss in the urine, among kidney transplant patients that develop during pregnancy or the postpartum period (a condition called preeclampsia). No increased risk of serious congenital malformations associated with the use of Advagraf was found.

Advagraf passes into breast milk. Therefore, you should not breastfeed while taking Advagraf.

Driving and using machines

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

Advagraf contains lactose, sodium, and lecithin (from soy)

Advagraf contains lactose (milk sugar). If your doctor has told you that you have an intolerance to some sugars, consult them before taking this medicine.

This medicine contains less than 1 mmol of sodium (23 mg) per capsule; this is essentially “sodium-free”.

The printing ink used in the Advagraf capsules contains soy lecithin. If you are allergic to peanuts or soy, talk to your doctor to determine if you should take this medicine.

3. How to take Advagraf

Follow the instructions for administration of Advagraf exactly as told by your doctor. If you are unsure, consult your doctor or pharmacist again. This medicine should only be prescribed by a doctor with experience in the treatment of patients with transplants.

Make sure you receive the same medicine with tacrolimus each time you collect your prescription, unless your transplant specialist has agreed to change to another medicine with tacrolimus. This medicine should be taken once daily. If the appearance of this medicine is not the same as usual, or if the dosing instructions have changed, consult your doctor or pharmacist as soon as possible to ensure you have the correct medicine.

The initial dose to prevent rejection of your transplanted organ will be determined by your doctor based on your body weight. The daily initial doses immediately after transplantation will generally be within the range of

0.10 – 0.30 mg per kg body weight and per day

depending on the transplanted organ. For the treatment of rejection, these same doses may be used.

Your dose depends on your overall condition and any other immunosuppressive medication you may be taking.

After starting treatment with Advagraf, your doctor will perform frequent blood tests to determine the correct dose. Afterward, your doctor will need to perform blood tests regularly to determine the correct dose and to adjust the dose from time to time. Your doctor will usually decrease your dose of Advagraf once your condition has stabilized. Your doctor will tell you exactly how many capsules to take.

You will need to take Advagraf every day until you continue to need immunosuppression to prevent rejection of your transplanted organ. You should stay 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 one hour until the next meal. Take the capsules immediately after removing them from the blister pack. The capsules should be swallowed wholewith a glass of water. Do not swallow the desiccant contained in the aluminum bag.

If you take more Advagraf than you should

If you accidentally take more Advagraf than you should, contact your doctor or go to the emergency department of the nearest hospital.

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 treatment with Advagraf

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

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Advagraf reduces the body's defense mechanisms (immune system), which will not work as well to fight infections. Therefore, if you are taking Advagraf, you will be more prone to infections.

Some infections can be serious or fatal and may include infections caused by bacteria, viruses, fungi, parasites, or other infections.

Inform your doctor immediately if you have symptoms of an infection, including:

• Fever, cough, sore throat, feeling of weakness or general malaise
• Memory loss, problems thinking, difficulty walking, or loss of vision - these symptoms may be due to a rare and serious brain infection (progressive multifocal leukoencephalopathy or PML)

Severe effects can occur, including allergic reactions and anaphylaxis. Benign and malignant tumors have been reported after treatment with Advagraf.

Inform your doctor immediately if you suspect you are suffering from any of the following serious adverse effects:

Frequent serious adverse effects (may affect up to 1 in 10 people):

• Gastrointestinal perforation: severe abdominal pain accompanied or not by other symptoms such as chills, fever, nausea, or vomiting.
• Insufficient function of the transplanted organ.
• Blurred vision.

Infrequent serious adverse effects (may affect up to 1 in 100 people):

• Thrombotic microangiopathy (lesions in small blood vessels) including hemolytic uremic syndrome with the following symptoms: low or no urine output (acute renal failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and bruising or abnormal bleeding and signs of infection.

Rare serious adverse effects (may affect up to 1 in 1,000 people):

• Thrombotic thrombocytopenic purpura: includes lesions in small blood vessels and is characterized by fever and bruising under the skin that can appear as red spots, with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), with symptoms of acute renal failure (low or no urine output), loss of vision, and seizures.
• Toxic epidermal necrolysis: erosion and blistering of the skin or mucous membranes, red and swollen skin that can peel off in large areas of the body.
• Blindness.

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

• Stevens-Johnson syndrome: unexplained generalized skin pain, facial swelling, severe illness with blistering of the skin, mouth, eyes, and genitals, rash, swelling of the tongue, red or purple skin rash that spreads, peeling of the skin.
• Torsades de pointes: change in heart rate that may or may not be accompanied by symptoms such as chest pain (angina), fainting, dizziness, or nausea, palpitations (feeling heartbeats) and difficulty breathing.

Adverse effects of unknown frequency (frequency cannot be estimated from available data):

• Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.
• Benign and malignant tumors have been reported after treatment as a result of immunosuppression, including malignant skin cancers and a rare type of cancer that can include skin lesions known as Kaposi's sarcoma. Symptoms include skin changes such as new colors or changes in existing ones, lesions, or lumps.
• Cases of pure red cell aplasia (a significant reduction in red blood cell count), hemolytic anemia (reduction in the number of red blood cells due to abnormal rupture of them accompanied by fatigue), and febrile neutropenia (a decrease in the type of white blood cells that fight infections, accompanied by fever) have been reported. The exact frequency of these adverse effects is unknown. You may not have symptoms or, depending on the severity of the condition, you may feel: fatigue, apathy, abnormal paleness of the skin (pallor), difficulty breathing, dizziness, headache, chest pain, and feeling cold in hands and feet.
• Cases of agranulocytosis (a significant decrease in the number of white blood cells accompanied by sores in the mouth, fever, and infection(s)) have been reported. You may not have symptoms or you may feel sudden fever, chills, and sore throat.
• Allergic reactions and anaphylaxis with the following symptoms: sudden itchy skin rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which can cause difficulty swallowing or breathing), and you may feel like you are going to faint.
• Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood changes, seizures, and vision changes. 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 (optic nerve disorder): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.

After receiving Advagraf, the following adverse effects can also occur and may be serious:

Very frequent adverse effects (may affect more than 1 in 10 people):

• Increased blood sugar, diabetes mellitus, increased potassium in the blood.
• Difficulty sleeping.
• Tremors, headache.
• Increased blood pressure.
• Abnormalities in liver function tests.
• Diarrhea, nausea.
• Kidney problems.

Frequent adverse effects (may affect up to 1 in 10 people):

• Reduction in the number of blood cells (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell counts (see blood test).
• Reduction of magnesium, phosphate, potassium, calcium, or sodium in the blood, fluid overload, increased uric acid or lipids in the blood, decreased appetite, increased blood acidity, other changes in blood salts (see blood test).
• Symptoms of anxiety, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders.
• Seizures, disorders of consciousness level, tingling and numbness (sometimes painful) in hands and feet, dizziness, decreased ability to write, nervous system disorders.
• Increased sensitivity to light, eye disorders.
• Ringing in the ears.
• Reduced blood flow in the heart vessels, faster heart rate.
• Bleeding, partial or complete blockage of blood vessels, decreased blood pressure.
• Shortness of breath, changes in lung tissue, fluid accumulation around the lungs, inflammation of the pharynx, cough, flu-like symptoms.
• Inflammations or ulcers that cause abdominal pain or diarrhea, stomach bleeding, mouth ulcers, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, abdominal swelling, loose stools, stomach problems.
• Bile duct disorders, yellowing of the skin due to liver problems, liver tissue damage, and liver inflammation.
• Itching, rash, hair loss, acne, increased sweating.
• Pain in the joints, limbs, back, and feet, muscle spasms.
• Insufficient kidney function, reduced urine production, difficulty or pain when urinating.
• General weakness, fever, fluid accumulation in the body, pain, and discomfort, increased alkaline phosphatase in the blood, weight gain, altered temperature sensation.

Infrequent adverse effects (may affect up to 1 in 100 people):

• Changes in blood coagulation, reduction in the number of all types of blood cells (see blood test).
• Dehydration.
• Reduction of proteins or sugar in the blood, increased phosphate in the blood.
• Coma, brain bleeding, stroke, paralysis, brain disorders, speech and language disorders, memory problems.
• Cataract.
• Hearing impairment.
• Irregular heartbeat, cardiac arrest, decreased heart performance, heart muscle disorders, increased heart size, stronger heartbeat, abnormal ECG, abnormal heart rate and pulse.
• Blood clot in a limb vein, shock.
• Breathing difficulties, respiratory tract disorders, asthma.
• Intestinal obstruction, increased blood amylase level, reflux of stomach contents into the throat, delayed stomach emptying.
• Skin inflammation, sunburn sensation.
• Joint disorders.
• Difficulty urinating, painful and abnormal menstrual bleeding.
• Multi-organ failure, catarrhal disease, increased sensitivity to heat and cold, feeling of pressure in the chest, restlessness or abnormal sensation, increased lactate dehydrogenase in the blood, weight loss.

Rare adverse effects (may affect up to 1 in 1,000 people):

• Small skin bleeding due to blood clots.
• Increased muscle stiffness.
• Deafness.
• Fluid accumulation around the heart.
• Acute shortness of breath.
• Pancreatic cyst formation.
• Liver blood flow problems.
• Increased hairiness.
• Thirst, falls, feeling of chest stiffness, decreased mobility, ulcer.

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

• Muscle weakness.
• Abnormal cardiac ultrasound.
• Liver failure.
• Pain when urinating, with blood in the urine.
• Increased fatty tissue.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Advagraf

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date that appears on the packaging after "EXP". The expiration date is the last day of the month indicated.

Use all hard prolonged-release capsules within the year following the opening of the aluminum pouch.

Store in the original packaging to protect it from moisture.

Medicines should not be disposed of through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Advagraf

• The active ingredient is tacrolimus.

Each 0.5 mg Advagraf capsule contains 0.5 mg of tacrolimus (as monohydrate).

Each 1 mg Advagraf capsule contains 1 mg of tacrolimus (as monohydrate).

Each 3 mg Advagraf capsule contains 3 mg of tacrolimus (as monohydrate).

Each 5 mg Advagraf capsule contains 5 mg of tacrolimus (as monohydrate).

• Other ingredients are:

Capsule content: Hypromellose, ethylcellulose, lactose, magnesium stearate.

Capsule shell: Titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), sodium lauryl sulfate, gelatin.

Printing ink: Shellac, soy lecithin, simethicone, red iron oxide (E 172), hydroxypropylcellulose.

Appearance of the Product and Package Contents

Advagraf 0.5 mg hard prolonged-release capsules are hard gelatin capsules printed in red with "0.5 mg" on the light yellow capsule shell and "? 647" on the orange capsule body, containing white powder.

Advagraf 0.5 mg is supplied as blister strips or precut unit-dose blisters with 10 capsules inside a protective aluminum pouch, which includes a desiccant. Packs of 30, 50, and 100 hard prolonged-release capsules are available in blisters and packs of 30x1, 50x1, and 100x1 hard prolonged-release capsules are available in precut unit-dose blisters.

Advagraf 1 mg hard prolonged-release capsules are hard gelatin capsules printed in red with "1 mg" on the white capsule shell and "? 677" on the orange capsule body, containing white powder.

Advagraf 1 mg is supplied as blister strips or precut unit-dose blisters with 10 capsules inside a protective aluminum pouch, which includes a desiccant. Packs of 30, 50, 60, and 100 hard prolonged-release capsules are available in blisters and packs of 30x1, 50x1, 60x1, and 100x1 hard prolonged-release capsules are available in precut unit-dose blisters.

Advagraf 3 mg hard prolonged-release capsules are hard gelatin capsules printed in red with "3 mg" on the orange capsule shell and "? 637" on the orange capsule body, containing white powder.

Advagraf 3 mg is supplied as blister strips or precut unit-dose blisters with 10 capsules inside a protective aluminum pouch, which includes a desiccant. Packs of 30, 50, and 100 hard prolonged-release capsules are available in blisters and packs of 30x1, 50x1, and 100x1 hard prolonged-release capsules are available in precut unit-dose blisters.

Advagraf 5 mg hard prolonged-release capsules are hard gelatin capsules printed in red with "5 mg" on the gray-red capsule shell and "? 687" on the orange capsule body, containing white powder.

Advagraf 5 mg is supplied as blister strips or precut unit-dose blisters with 10 capsules inside a protective aluminum pouch, which includes a desiccant. Packs of 30, 50, and 100 hard prolonged-release capsules are available in blisters and packs of 30x1, 50x1, and 100x1 hard prolonged-release capsules are available in precut unit-dose blisters.

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

Netherlands

Manufacturer:

Astellas Ireland Co., Ltd.

Killorglin, County Kerry, V93FC86

Ireland

You can obtain more information about this medicine by contacting the local representative of the Marketing Authorization Holder:

Date of Last Revision of this Prospectus:

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