Patient Information Leaflet

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

• Keep this leaflet, as you may need to read it again.
• If you are unsure about anything, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others even if they have similar symptoms to you, as it may harm them.
• If you experience any side effects, consult your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

1.What is Advagraf and what it is used for

2.What you need to know before you start taking Advagraf

3.How to take Advagraf

4.Possible side effects

5.Storage of Advagraf

6.Contents of the pack and additional information

Advagraf contains the active ingredient tacrolimus. It is an immunosuppressant. After an organ transplant (liver, kidney), the immune system of your body will attempt to reject the new organ. Advagraf is used to control the immune response of your body, allowing you to accept the transplanted organ.

You may also receive Advagraf to treat a rejection that is occurring in your liver, kidney, heart, or other transplanted organ, when any previous treatment you were following, fails to control this immune response after your transplant.

Advagraf is used in adults.

Do not take Advagraf

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

Warnings and precautions

Prograf and Advagraf both contain the active ingredient, tacrolimus. However, Advagraf is taken once a day, while Prograf is taken twice a day. This is because the capsules of Advagraf allow for a 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 medication (listed below in “Use of Advagraf with other medications”)
• if you have or have had liver problems
• if you have had diarrhea for more than a day
• if you have severe abdominal pain accompanied or not by other symptoms, such as chills, fever, nausea, or vomiting
• if you have a heart rhythm disorder called “prolongation of the QT interval”
• if you have or have had small blood vessel injuries, known as microangiopathy thrombotic/purpura thrombocytopenic thrombotic/syndrome hemolytic urémic. Inform your doctor if you develop fever, skin hematomas (may appear as red spots), inexplicable fatigue, confusion, yellow discoloration of the skin or eyes, decreased urine output, vision loss, 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 herbal product, as this may affect the effectiveness and dose of Advagraf that you need to receive. If you have any doubts, please consult your doctor before taking any herbal product or preparation.

Your doctor may need to adjust your dose of Advagraf.

You should maintain regular contact with your doctor. Occasionally, to establish the appropriate dose of Advagraf, your doctor may need to perform blood and urine tests, cardiac tests, and eye tests.

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

Precautions for handling:

During preparation, avoid contact with any part of the body, such as the skin or eyes, as well as breathing near the solutions for injection, powder, or granules contained in 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 old.

Other medications and Advagraf

Inform your doctor or pharmacist if you are using or have recently used any other medication, including those purchased without a prescription and herbal medications.

Advagraf should not be used with cyclosporine (another medication used to prevent organ transplant rejection).

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

The blood levels of Advagraf may be affected by other medications you are taking, and the blood levels of other medications may be affected by the administration of Advagraf, which may requirethe interruption,increase, or decrease of the Advagraf dose.

Some patients have experienced increases in tacrolimus blood levels while taking other medications.This could cause severe adverse effects, such as kidney problems, nervous system problems, and heart rhythm disorders (see section4).

The effect on Advagraf blood levels can occur very soon after starting to use another medication, so it may be necessary to monitor the Advagraf blood level frequently and continuously during the first days of use of another medication and frequently while continuing its use.Some other medications may cause tacrolimus blood levels to decrease, which may increase the risk of organ transplant rejection.Particularly, you should inform your doctor if you are taking or have recently taken medications 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 human cytomegalovirus (CMV)
• HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), the potentiator cobicistat, and HIV combination tablets or non-nucleoside reverse transcriptase inhibitors (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 transplant rejection prevention
• medications for stomach ulcers and acid reflux (e.g., omeprazole, lansoprazole, or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g., metoclopramide)
• cisapride or antacids containing magnesium hydroxide and aluminum, used to treat acid reflux
• oral contraceptives or other hormone treatments with ethinylestradiol, hormone treatments with danazol
• medications used to treat high blood pressure or heart problems (e.g., nifedipine, nicardipine, diltiazem, and verapamil)
• antiarrhythmic medications (amiodarone) used to control irregular heartbeats
• 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
• herbal medications containing St. John's Wort (Hypericum perforatum) or Schisandra sphenanthera extracts
• cannabidiol (its use includes, among others, the treatment of epilepsy seizures).

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

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

Inform your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken with sirolimus or everolimus, the risk of microangiopathy thrombotic, purpura thrombocytopenic thrombotic, and hemolytic urémic 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 nephropathy (e.g., amiloride, triamterene, or spironolactone), or trimethoprim and cotrimoxazole antibiotics that may increase potassium levels in your blood, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen) used to treat fever, inflammation, and pain, anticoagulants (that prevent blood clotting), or oral medications for diabetes treatment while taking Advagraf.

If you plan to be vaccinated, consult your doctor.

Taking Advagraf with food and drinks

Avoid grapefruit (also in juice) while taking Advagraf, as it may affect your blood levels.

Pregnancy and breastfeeding

If you are pregnant, think you may be pregnant, or plan to become pregnant, consult your doctor before using Advagraf. A study evaluated the outcomes of pregnancy in women treated with tacrolimus and other immunosuppressants. Although there was not enough evidence to draw conclusions in this study, there were reported higher rates of spontaneous abortion 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 develops during pregnancy or the postpartum period (a condition called preeclampsia). There was no increased risk of severe congenital malformations associated with Advagraf use.

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

Driving and operating machinery

Do not drive and do not operate tools or machines if you feel dizzy or drowsy, or have difficulty seeing clearly after taking Advagraf. These effects are more common if you also take alcohol.

Advagraf contains lactose, sodium, and lecithin (soya)

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

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

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

Follow exactly the administration instructions for Advagraf indicated by your doctor. In case of doubt, consult your doctor or pharmacist again. This medication should only be prescribed by a doctor with experience in treating patients with transplants.

Ensure that you receive the same medication with tacrolimus each time you pick up your prescription, unless your transplant specialist has agreed to switch to another medication different from tacrolimus. This medication should be taken once a day. If the appearance of this medication is not the same as always, or if the dosing instructions have changed, consult your doctor or pharmacist as soon as possible to ensure that you have the correct medication.

The initial dose to prevent rejection of your transplanted organ will be set by your doctor, calculated according to your body weight. The initial daily doses immediately after the transplant will generally be within the range of

0.10–0.30mg per kg of body weight and per day

depending on the transplanted organ. To treat rejection, these same doses may be used.

Your dose will depend on your general condition, and any other immunosuppressive medication you may be taking.

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

You will need to take Advagraf every day until you no longer need immunosuppression to prevent rejection of your transplanted organ. You should maintain regular contact with your doctor.

Advagraf should be taken orally once a day, in the morning. Take Advagraf with an empty stomach or 2-3 hours after a meal.Wait at least one hour until the next meal.Take the capsules immediately after removing them from the blister.The capsules should be swallowedwholewith 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 nearest hospital emergency department.

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 interrupt 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 doubts about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience 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 severe 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 weak or generally unwell
• Memory loss, difficulty thinking, difficulty walking, or loss of vision – these symptoms may be due to a rare and severe brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML)

Severe side effects may 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 experiencing any of the following severe side effects:

Common severe side effects (may affect up to 1 in 10 people):

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

Less common severe side effects (may affect up to 1 in 100 people):

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

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

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

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

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

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

• Oportunist infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.
• Cancers, including skin cancers and a rare type of cancer that may include skin lesions known as Kaposi's sarcoma, have been reported after treatment with tacrolimus, including Advagraf. Symptoms include changes in the skin such as new colors or changes to existing ones, lesions, or lumps.
• Pure red cell aplasia (a very significant reduction in red blood cell count), hemolytic anemia (a decrease in red blood cell count due to abnormal rupture of these cells 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 side effects is unknown. You may not have symptoms or, depending on the severity of your condition, you may feel: fatigue, apathy, abnormal paleness of the skin (pallor), difficulty breathing, dizziness, headache, chest pain, and a feeling of coldness in your hands and feet.
• Agranulocytosis (a significant decrease in white blood cell count accompanied by mouth sores, fever, and infection(s)). You may not have symptoms or may feel fever, chills, and sudden sore throat.
• Allergic reactions and anaphylaxis with the following symptoms: sudden itching rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing) and may feel like you are going to faint.
• Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood changes, seizures, and visual disturbances. These may be signs of a condition known as posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus, including Advagraf.
• Optic neuropathy (alteration of the optic nerve): vision problems such as blurred vision, changes in color vision, difficulty seeingdetailsor reduced visual field.

After receivingAdvagrafyou may also experience the following side effects, which may be severe:

Very common side 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.
• Abnormal liver function tests.
• Diarrhea, nausea.
• Renal problems.

Common side 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 count (see blood test).
• Reduction in 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).
• Anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders.
• Seizures, altered level of consciousness, tingling and numbness (sometimes painful) in hands and feet,migraines, decreased ability to write, nervous system disorders.
• Increased sensitivity to light, eye disorders.
• Tinnitus.
• Reduced blood flow in heart vessels, faster heart rate.
• Bleeding, partial or complete blockage of blood vessels, reduced blood pressure.
• Shortness of breath, changes in lung tissue, fluid accumulation around the lungs, pharyngitis, cough, flu-like symptoms.
• Inflammations or ulcers that cause abdominal pain or diarrhea, bleeding in the stomach, inflammation or ulcers in the mouth, fluid accumulation in the intestine, vomiting, abdominal pain, indigestion, constipation, flatulence, abdominal swelling, loose stools, gastrointestinal 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.
• Joint pain, extremities, back, and foot pain, muscle spasms.
• Renal insufficiency, reduced urine production, limited or painful urination.
• General weakness, fever, fluid accumulation in the body, pain and discomfort, increased alkaline phosphatase in the blood, weight gain, altered body temperature.

Less common side effects (may affect up to 1 in 100 people):

• Changes in blood clotting, reduction in the number of all types of blood cells (see blood test).
• Dehydration.
• Reduction in blood proteins or sugar, increased phosphate in the blood.
• Coma, cerebral hemorrhage, stroke, paralysis, brain disorders, speech and language abnormalities, memory problems.
• Corneal opacity.
• Decreased hearing.
• Irregular heartbeat, cardiac arrest, decreased heart function, heart muscle disorders, increased heart muscle size, faster heartbeat, abnormal ECG, abnormal heart rate and pulse.
• Thrombosis in a vein of a limb, shock.
• Respiratory difficulties, respiratory tract disorders, asthma.
• Intestinal obstruction, increased amylase levels in the blood, gastroesophageal reflux, delayed stomach emptying.
• Skin inflammation, sunburn sensation.
• Joint disorders.
• Inability to urinate, painful menstruation, and abnormal menstrual bleeding.
• Multi-organ failure, catarrhal disease, increased sensitivity to heat and cold, chest pressure sensation, restlessness or abnormal sensation, increased lactate dehydrogenase in the blood, weight loss.

Rare side 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.
• Problems with blood flow in the liver.
• Increased hairiness.
• Thirst, falls, chest stiffness, decreased mobility, ulcer.

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

• Muscle weakness.
• Abnormal echocardiogram.
• Liver insufficiency.
• Painful urination with blood in the urine.
• Increased body fat.

Reporting side effects

If you experienceany type of side effect, consult your doctor or pharmacist, even if it is apossibleside effect that does not appear in this leaflet.You can also report them directly through thenational reporting system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the packaging after “CAD”. The expiration date is the last day of the month indicated.

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

Store in the original packaging to protect it from moisture.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and unused medications. This will help protect the environment.

Composition of Advagraf

• The active ingredient is tacrolimus.

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

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

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

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

• The other components are:

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

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

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

Appearance of the product and contents of the package

Advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules printed in red with “0.5 mg” on the yellowish clear cap of the capsule and “?647”on the orange body of the capsule, containing white powder.

Advagraf 0.5 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in an aluminum protective packaging, which includes a desiccant. It is available in packaging of 30, 50, and 100 prolonged-release hard capsules in blisters and in packaging of 30x1, 50x1, and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters.

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

Advagraf 1 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in an aluminum protective packaging, which includes a desiccant. It is available in packaging of 30, 50, 60, and 100 prolonged-release hard capsules in blisters and in packaging of 30x1, 50x1, 60x1, and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters.

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

Advagraf 3 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in an aluminum protective packaging, which includes a desiccant. It is available in packaging of 30, 50, and 100 prolonged-release hard capsules in blisters and in packaging of 30x1, 50x1, and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters.

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

Advagraf 5 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in an aluminum protective packaging, which includes a desiccant. It is available in packaging of 30, 50, and 100 prolonged-release hard capsules in blisters and in packaging of 30x1, 50x1, and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters.

Only some package sizes may be marketed.

Marketing Authorization Holder and Responsible Person for Manufacturing

Marketing Authorization Holder:

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

Netherlands

Responsible Person for Manufacturing:

Astellas Ireland Co., Ltd.

Killorglin, County Kerry, V93FC86

Ireland

For more information about this medicinal product, please contact the local representative of the marketing authorization holder:

Last update of the summary of product characteristics:

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