Advagraf 0.5 mg prolonged-release hard capsules

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

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

Tacrolimus

Read the entire 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 have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only, and you should not give it to other people, even if they have the same symptoms as you, because it could harm them.
• If you experience any adverse reactions, consult your doctor or pharmacist, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

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

1. What Advagraf is and what it is used for

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

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

Advagraf is used in adults.

2. What you need to know before taking Advagraf

Do not take Advagraf

• if you are allergic (hypersensitive) to tacrolimus or 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 same active substance, tacrolimus. However, Advagraf is taken once daily, whereas Prograf is taken twice daily. This is because Advagraf capsules provide prolonged release (slower release over a longer period of time) of tacrolimus. Advagraf and Prograf are not interchangeable.

Consult your doctor or pharmacist before starting to take Advagraf:

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

Please avoid taking any herbal preparations, e.g., St. John’s wort (Hypericum perforatum) or any other herbal products, as they may affect the effectiveness and required dose of Advagraf. 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. Periodically, your doctor may need to perform blood and urine tests, heart examinations, and eye examinations to determine the appropriate dose of Advagraf.

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 appropriate 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, with the injection solutions, powder, or granules contained in tacrolimus products, as well as inhalation near these substances. If such contact occurs, wash the skin and eyes thoroughly.

Children and adolescents

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

Other medicines and Advagraf

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

The use of Advagraf with cyclosporine (another medicine used to prevent organ transplant rejection) is not recommended.

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 your transplant specialist if you require another medicine that could increase or decrease your blood levels of tacrolimus.

Blood levels of Advagraf may be altered by other medicines you are taking, and blood levels of other medicines may be altered by taking Advagraf, which may require interruption, increase, or decrease in the dose of Advagraf.

Some patients have experienced increased blood levels of tacrolimus while taking other medicines. This could lead to serious adverse effects such as kidney problems, nervous system disorders, and heart rhythm disturbances (see section 4).

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

• antifungal and antibiotic medicines, 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 drug cobicistat, and combined HIV 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 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
• oral contraceptive pill or other hormonal treatments containing 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
• herbal medicines containing St. John’s wort (Hypericum perforatum) or extracts of Schisandra sphenanthera
• cannabidiol (used, among others, for the treatment of epileptic seizures).

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

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

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

Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, high blood pressure, and nephropathy (e.g., amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim and cotrimoxazole, which may 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 plan to be vaccinated, consult your doctor.

Taking Advagraf with food and drink

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

Pregnancy and breastfeeding

If you are pregnant, think you might be pregnant, or plan to become pregnant, consult your doctor before using Advagraf. A study evaluated pregnancy outcomes in women treated with tacrolimus and other immunosuppressants. Although this study did not provide sufficient 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 during pregnancy or the postpartum period (a condition called preeclampsia) among kidney transplant patients. No increased risk of major congenital malformations associated with the use of Advagraf was found.

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

Driving and using machines

Do not drive and do not operate tools or machinery if you feel dizzy or drowsy, or have problems seeing clearly after taking Advagraf. These effects are more likely if you also consume alcohol.

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

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

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

The printing ink used on Advagraf capsules contains soy lecithin. If you are allergic to peanuts or soy, speak with your doctor to determine whether you should take this medicine.

3. How to take Advagraf

Follow exactly the instructions for taking Advagraf as given by your doctor. If you are unsure, consult your doctor or pharmacist again. This medicine should only be prescribed by a doctor experienced in the treatment of transplant patients.

Make sure you receive the same tacrolimus medicine each time you collect your prescription, unless your transplant specialist has agreed to switch to a different tacrolimus medicine. This medicine should be taken once daily. If this medicine looks different than 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 initial daily doses just after transplantation are generally within the range of

0.10 – 0.30 mg per kg of body weight per day

depending on the transplanted organ. These same doses may be used to treat rejection.

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

After starting treatment with Advagraf, your doctor will perform frequent blood tests to determine the correct dose. Afterwards, your doctor will need to carry out regular blood tests to establish 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 to take.

You will need to take Advagraf every day for as long as you require immunosuppression to prevent rejection of your transplanted organ. You should maintain 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 before the next meal. Take the capsules immediately after removing them from the blister pack. The capsules must be swallowed whole with a glass of water. Do not swallow the desiccant contained in the aluminum pouch.

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 forget to take your Advagraf capsules in the morning, take them as soon as possible on the same day. Do not take a double dose the following morning.

If you stop taking Advagraf

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

If you have any further 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 everyone will experience them.

Advagraf reduces the defence mechanisms of your body (immune system), so it will not work as effectively in fighting infections. Therefore, if you are taking Advagraf, you will be more prone to infections.

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

Inform your doctor immediately if you 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 very rare and serious brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML)

Serious adverse effects may occur, including allergic and anaphylactic reactions. 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 serious adverse effects:

Frequent serious adverse 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.
• Inadequate function of your transplanted organ.
• Blurred vision.

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

• Thrombotic microangiopathy (damage to the smallest 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), 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 damage to the smallest blood vessels and is characterized by fever and bruising under the skin that may appear as red spots, with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), 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 serious adverse effects (may affect up to 1 in 10,000 people):

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

Serious adverse effects with 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 may include skin lesions known as Kaposi's sarcoma. Symptoms include skin changes such as new discolorations or changes in existing ones, lesions, or lumps.
• Cases of pure red cell aplasia (a marked reduction in red blood cell count), hemolytic anemia (decrease in red blood cells due to abnormal breakdown, accompanied by fatigue), and febrile neutropenia (a reduction 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 have no symptoms, or depending on the severity, you may experience: fatigue, apathy, abnormal paleness of the skin (pallor), difficulty breathing, dizziness, headache, chest pain, and cold sensation in hands and feet.
• Cases of agranulocytosis (a marked decrease in white blood cells accompanied by mouth ulcers, fever, and infection(s)). You may have no symptoms or may suddenly experience fever, chills, and sore throat.
• Allergic and anaphylactic reactions with the following symptoms: sudden itchy skin rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and feeling faint.
• Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood changes, seizures, and visual disturbances. 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 (damage to the optic nerve): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.

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

Very common 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.

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

• Reduction in blood cells (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell counts (see blood tests).
• 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 tests).
• Anxiety symptoms, confusion and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders.
• Seizures, disturbances in level of consciousness, tingling and numbness (sometimes painful) in hands and feet, dizziness, reduced ability to write, nervous system disorders.
• Increased sensitivity to light, eye disorders.
• Ringing in the ears.
• Reduced blood flow in coronary vessels, faster heartbeat.
• Bleeding, partial or complete blockage of blood vessels, reduced 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 causing abdominal pain or diarrhea, stomach bleeding, mouth ulcers or inflammation, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, bloating, loose stools, stomach problems.
• Biliary tract disorders, yellowing of the skin due to liver problems, liver tissue damage, and liver inflammation.
• Itching, rash, hair loss, acne, increased sweating.
• Joint, limb, back, and foot pain, muscle spasms.
• Kidney insufficiency, reduced urine output, difficulty or pain when urinating.
• General weakness, fever, fluid accumulation in the body, pain and discomfort, increased blood alkaline phosphatase enzyme, weight gain, sensation of altered temperature.

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

• Changes in blood clotting, reduction in all types of blood cells (see blood tests).
• Dehydration.
• Reduction in proteins or blood sugar, increased blood phosphate.
• Coma, brain hemorrhage, stroke, paralysis, brain disorders, speech and language abnormalities, memory problems.
• Cataracts.
• Hearing deterioration.
• Irregular heartbeat, cardiac arrest, reduced heart performance, heart muscle disorders, enlarged heart muscle, stronger heartbeat, abnormal ECG, abnormal heart rate and pulse.
• Blood clot in a vein of a limb, shock.
• Breathing difficulties, respiratory tract disorders, asthma.
• Intestinal obstruction, increased blood level of amylase enzyme, reflux of stomach contents into the throat, delayed stomach emptying.
• Skin inflammation, burning sensation in sunlight.
• Joint disorders.
• Inability to urinate, painful menstruation, abnormal menstrual bleeding.
• Multi-organ failure, catarrhal-type illness, increased sensitivity to heat and cold, chest pressure sensation, restlessness or abnormal sensation, increased blood lactate dehydrogenase enzyme, weight loss.

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

• Small skin bleeds due to blood clots.
• Increased muscle rigidity.
• Deafness.
• Fluid accumulation around the heart.
• Acute shortness of breath.
• Cyst formation in the pancreas.
• Problems with blood flow in the liver.
• Increased hair growth.
• Thirst, falls, chest tightness, reduced 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, blood in the urine.
• Increased fatty tissue.

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide 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 expiry date stated on the packaging after "EXP". The expiry date is the last day of the month indicated.

Use all prolonged-release hard capsules within one year after opening the aluminium bag.

Store in the original packaging to protect from moisture.

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

6. Contents of the pack and other information

Composition of Advagraf

• The active substance 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:

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

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

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

Appearance of the product and contents of the pack

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

Advagraf 0.5 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in a protective aluminium overwrap containing a desiccant. Packs containing 30, 50 and 100 prolonged-release hard capsules in blisters and packs containing 30x1, 50x1 and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters are available.

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

Advagraf 1 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in a protective aluminium overwrap containing a desiccant. Packs containing 30, 50, 60 and 100 prolonged-release hard capsules in blisters and packs containing 30x1, 50x1, 60x1 and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters are available.

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

Advagraf 3 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in a protective aluminium overwrap containing a desiccant. Packs containing 30, 50 and 100 prolonged-release hard capsules in blisters and packs containing 30x1, 50x1 and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters are available.

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

Advagraf 5 mg is supplied as blister strips or pre-cut single-dose blisters with 10 capsules in a protective aluminium overwrap containing a desiccant. Packs containing 30, 50 and 100 prolonged-release hard capsules in blisters and packs containing 30x1, 50x1 and 100x1 prolonged-release hard capsules in pre-cut single-dose blisters are available.

Only certain pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

The Netherlands

Manufacturer:

Astellas Ireland Co., Ltd.

Killorglin, County Kerry, V93FC86

Ireland

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

Date of the most recent review of this leaflet:

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