MODIGRAF 1 mg GRANULES FOR ORAL SUSPENSION

Introduction

Package Leaflet: Information for the User

Modigraf 0.2mg, granules for oral suspension

Modigraf 1mg, granules for oral suspension

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

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

1. What is Modigraf and what is it used for

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

You may also receive Modigraf for treatment of rejection that is occurring in your liver, kidney, heart or other transplanted organ, or if any previous treatment you were following did not control this immune response after your transplant.

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 organ transplant rejection) 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 had diarrhea for more than one day
• if you feel strong abdominal pain accompanied by other symptoms such as chills, fever, nausea or vomiting
  • if you have a heart condition called "QT prolongation"
  • if you have or have had damage to small blood vessels, known as microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Tell your doctor if you develop fever, bruising under the skin (which can appear as red spots), unexplained tiredness, 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 products, as this may affect the effectiveness and the dose of Modigraf you need to receive. If you are in doubt, please consult your doctor before taking any plant-based product or preparation.

Your doctor may need to adjust your dose of Modigraf.

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

You should limit your exposure to sunlight and UV (ultraviolet) light while taking Modigraf. This is because immunosuppressants like Modigraf can increase the risk of skin cancer. In case of sun exposure, 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 inhaling the solutions for injection, powder or granules contained in the tacrolimus products. If such contact occurs, wash the skin and eyes.

Other medicines and Modigraf

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

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

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

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

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 Modigraf blood levels can occur very soon after starting to use another medicine, so it may be necessary to monitor the blood level of Modigraf 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 tell 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 pharmacokinetic enhancer cobicistat, and non-nucleoside reverse transcriptase inhibitors (e.g. 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 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, hormonal treatments with ethinylestradiol, or hormonal treatments with danazol
• medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem, and verapamil)
• antiarrhythmic medicines (amiodarone) used to control 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 your 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 your blood levels of tacrolimus and make necessary dose adjustments of Modigraf after starting treatment for hepatitis C.

Tell your doctor if you are taking or need to take ibuprofen (used to treat fever, inflammation, and pain), antibiotics (cotrimoxazole, vancomycin, or aminoglycoside antibiotics such as gentamicin), amphotericin B (used to treat fungal infections), 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 Modigraf.

Tell your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken with sirolimus or everolimus, the risk of 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 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 Modigraf.

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

Taking Modigraf with food and drinks

Modigraf should be taken on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal. Avoid grapefruit or grapefruit juice while taking Modigraf, as it may affect your blood levels.

Pregnancy and breastfeeding

If you take Modigraf during pregnancy, it may pass to your baby through the placenta. It could potentially affect your baby's health or harm the course of your pregnancy.

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before taking this medicine. A study evaluated pregnancy outcomes 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 anomalies was found with the use of Modigraf. Modigraf passes into breast milk. Therefore, you should not breastfeed while taking Modigraf.

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

Modigraf contains lactose and sodium

Modigraf 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 dose, which is essentially "sodium-free".

3. How to take Modigraf

Follow the instructions for administration of this medicine exactly as prescribed by your doctor. If you are in doubt, consult your doctor or pharmacist again. Modigraf should only be prescribed by doctors with experience in treating transplant patients and in the use of medicines that control the body's immune system (immunosuppressants).

Make sure you receive the same tacrolimus medicine each 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 the dosage 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 doses immediately after transplantation will generally be within the range of 0.075 - 0.30 mg per kg body weight per day, depending on the transplanted organ. For treatment of rejection, the same dose may be used.

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

Children and adolescents

Children and adolescents will receive Modigraf doses calculated in the same way as for adults. In general, children need higher doses per kg body weight to achieve the same effective blood levels as adults.

After starting your treatment with Modigraf, your doctor will perform frequent blood tests to determine the correct dose and to adjust the dose from time to time. Your doctor will usually decrease your dose of Modigraf once your condition has stabilized. 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 stay in regular contact with your doctor.

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

How to prepare Modigraf sachets for use

Your doctor will advise you on the number of sachets to open and the volume of water needed to make the suspension. To measure the volume of water accurately, you can use a syringe or a graduated container.

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 the water on a stable surface. Do not use cups or spoons made of PVC (polyvinyl chloride) to prepare Modigraf, as the active substance of Modigraf may stick to PVC.

Carefully open the prescribed number of sachets, for example, with scissors at the indicated point with an arrow. Hold the open sachet between your thumb and index finger over the cup with the water, with the open side of the sachet facing down. Gently tap the closed end of the sachet and pour the contents of each sachet into the glass or cup with water. Do not use any utensils or liquids to empty the sachet. If you follow these instructions, you will get the correct amount of granules from the sachet. It is normal for some granules to remain inside the sachet; the sachet is designed for this.

Shake or stir gently until the granules are completely suspended. The suspension can be drawn up with a syringe or the patient can take it directly. The liquid has a sweet taste. Rinse the glass or cup once with the same amount of water and drink it as well. The liquid should be drunk immediately after preparation.

If you take more Modigraf than you should

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

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 Modigraf, wait until it is time for your 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 treatment unless your doctor tells you to.

If you have any further questions on the use of this product, 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.

Modigraf reduces the body's defense mechanisms (immune system), which will not work as well when fighting infections. Therefore, if you are taking Modigraf, you will be more prone to suffering from 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 (a very severe type of allergic reaction with fainting and difficulty breathing, requiring immediate medical attention). Benign and malignant tumors have been reported after treatment with Modigraf.

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

Common 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.

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

• Thrombotic microangiopathy (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 serious adverse effects (may affect up to 1 in 1,000 people):

• Thrombocytopenic purpura: includes lesions in smaller 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 kidney 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, rashes, 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 colorations 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 red blood cell count due to abnormal breakdown of red blood 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 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 white blood cell count, accompanied by mouth ulcers, fever, and infection(s)) have been reported. You may not have symptoms or you may suddenly feel 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 (nerve damage): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.

After receiving Modigraf, the following adverse effects can 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.
• Abnormal liver function tests.
• Diarrhea, nausea.
• Kidney problems.

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

• Reduction in blood cell count (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell count (see blood test).
• Reduced 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, 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 coronary 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, throat inflammation, 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 joints, limbs, back, and feet, muscle spasms.
• Insufficient kidney function, reduced urine production, disorders 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.

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

• Changes in blood coagulation, reduction in all types of blood cells (see blood test).
• Dehydration.
• Reduced protein or sugar in the blood, increased phosphate in the blood.
• Coma, cerebral bleeding, stroke, paralysis, brain disorders, speech and language disorders, memory problems.
• Cataract.
• Hearing impairment.
• Irregular heartbeat, cardiac arrest, decreased cardiac output, heart muscle disorders, increased heart muscle 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.
• Urination disorders, painful and abnormal menstrual bleeding.
• Multi-organ failure, flu-like illness, increased sensitivity to heat and cold, chest pressure sensation, 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.
• Problems with blood flow in the liver.
• Increased hairiness.
• Thirst, falls, chest pressure sensation, decreased mobility, ulcers.

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

• Muscle weakness.
• Abnormal cardiac ultrasound.
• Liver failure.
• Painful urination, with blood in the urine.
• Increased fatty tissue.

Children and Adolescents

Children and adolescents may experience the same adverse effects as adults.

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 leaflet. 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 Modigraf

Keep this medicine out of sight and reach of children.

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

This medicine does not require any special storage temperature.

After preparation, the suspension should be administered immediately.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Modigraf

• 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 sodium croscarmellose (E468).

Appearance and Package Contents

Modigraf granules for oral suspension are white granules supplied in sachets.

They are marketed in boxes of 50 sachets.

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 Leaflet:

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