Product Information for the User

Modigraf 0.2mg, oral granule suspension

Modigraf 1mg, oral granule suspension

Tacrólimus

Read this entire product information carefully before starting to take this medication, as it contains important information for you.

• Keep this product information, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medication has been prescribed only for you, and you should not give it to others who have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this product information. See section 4.

1.What is Modigraf and what is it used for

2.What you need to know before starting to take Modigraf

3.How to take Modigraf

4.Possible adverse effects

5.Storage of Modigraf

6.Contents of the package and additional information

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

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

Modigraf is used in adults and children.

Do not take Modigraf

• If you are allergic to tacrolimus or any of the other components of this medication (listed in section 6).
• If you are allergic to sirolimus (another substance used to prevent rejection of your transplanted organ) or any macrolide antibiotic (e.g., erythromycin, clarithromycin, josamycin).

Warnings and precautions

Consult your doctor or pharmacist before starting to take Modigraf.

-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 microangiopathic thrombosis, thrombotic thrombocytopenic purpura, or hemolytic uremic syndrome. Inform your doctor if you develop fever, skin hemorrhages (which may appear as red spots), unexplained 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 Modigraf 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 Modigraf dose.

You should maintain regular contact with your doctor. Occasionally, to establish the appropriate dose of Modigraf, 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) radiation while taking Modigraf. This is because immunosuppressants like Modigraf may increase the risk of skin cancer. In case of sun exposure, 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 injection solutions, powder, or granules contained in the tacrolimus products. If such contact occurs, wash the skin and eyes.

Other medications and Modigraf

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

Modigraf is not recommended for use 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 levels..

Modigraf blood levels may be affected by other medications you are taking, and blood levels of other medications may be affected by Modigraf administration, which may require interruption, increase, or decrease of the Modigraf 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 arrhythmias (see section 4).

The effect on tacrolimus blood levels may occur very soon after starting to use another medication, so it may be necessary to monitor Modigraf blood levels 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 taken recently 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).

-protease inhibitors for HIV (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.

-protease inhibitors for HCV (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).

-micophenolic 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, hormone treatments with ethinylestradiol, or 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 arrhythmia (irregular heartbeat).

-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 products containing St. John's Wort (Hypericum perforatum) or Schisandra sphenanthera extracts.

-cannabidiol (its use includes, among others, the treatment of epilepsy).

• Inform your doctor if you are receiving treatment for hepatitis C. The pharmacological treatment for hepatitis C may change your liver function and 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 Modigraf 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 with Modigraf.

Inform your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken with sirolimus or everolimus, the risk of microangiopathic thrombosis, 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, 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 (which prevent blood clotting), or oral medications for diabetes treatment while taking Modigraf.

If you plan to be vaccinated, consult your doctor.

Modigraf with food and drinks

Generally, you should take Modigraf 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 may potentially influence your baby's health or harm the course of pregnancy.

If you are pregnant or breastfeeding, believe you may be pregnant, or intend to become pregnant, consult your doctor before using this medication.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, higher rates of spontaneous abortion were reported among patients with liver and kidney transplants treated with tacrolimus, as well as higher rates of persistent hypertension associated with protein loss in the urine among patients with kidney transplants that develops during pregnancy or the postpartum period (a condition called preeclampsia). No increased risk of severe congenital malformations was found associated with the use of Modigraf. Modigraf passes into breast milk. Therefore, do not breastfeed while taking Modigraf.

Driving and operating machines

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

Modigraf contains lactose and sodium

Modigraf contains lactose (milk sugar). If your doctor has told you that you have a certain sugar intolerance, consult with him before taking this medication.

This medication contains less than 1 mmol of sodium (23 mg); that is, it is essentially "sodium-free."

Follow exactly the administration instructions of this medication as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again. Modigraf should be prescribed by experienced doctors to treat transplanted patients and in the use of medications that control the body's immune system (immunosuppressants).

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 twice a day. If the physical appearance has changed from the normal white granule, or if the dosage 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 doses shortly after the transplant will generally be within the range of 0.075 – 0.30 mg per kg of body weight and per day, depending on the transplanted organ. For rejection treatment, the same dose may be used.

Your dose depends on your general condition, and other immunosuppressant medications you may be taking.

Children and adolescents

Children and adolescents will receive Modigraf doses calculated in the same way as those of adults. Generally, children need higher doses per kg of weight to achieve the same effective blood levels as adults.

After starting your treatment with Modigraf, your doctor will perform frequent blood tests to define the correct dose and to adjust the dose from time to time. Your doctor will usually reduce your Modigraf dose once your situation has stabilized. Your doctor will tell you exactly how many packets you should take.

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

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

How to prepare the Modigraf packets for use

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

Pour the prescribed volume of water (at room temperature) into a cup or glass, up to a maximum of 50 ml. Place the glass with the water on a stable surface. Do not use cups or spoons made of PVC (polyvinyl chloride) to prepare Modigraf because the active ingredient of Modigraf can adhere to PVC.

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

Shake or gently stir until the granule is completely suspended. The suspension can be taken 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 must be consumed 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 nearest hospital emergency department.

If you forget to take Modigraf

Do not take a double dose to compensate for the missed individual doses.

If you have forgotten to take Modigraf, wait until it is time for the next dose and continue as usual.

If you interrupt Modigraf treatment

Stopping your Modigraf treatment 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 product, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Modigraf reduces the body's defense mechanisms (immune system), which will not work as well to fight off infections. Therefore, if you are taking Modigraf, you will be more prone to getting 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 (a very severe allergic reaction with lightheadedness and difficulty breathing, which requires immediate medical attention). Benign and malignant tumors have been reported after treatment with Modigraf.

Inform your doctor immediately if you suspect you are experiencing any of the following severe side effects:

Severe side effects that are frequent (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 your transplanted organ.

• Blurred vision.

Severe side effects that are infrequent (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.

Severe side effects that are rare (may affect up to 1 in 1,000 people):

• Purpura thrombocytopenic thrombosis: includes lesions in smaller blood vessels and is characterized by fever and bruises under the skin that may 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), 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.

Severe side effects that are very rare (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: a change in heart rate that may or may not be accompanied by symptoms such as chest pain (angina), dizziness, nausea, palpitations (feeling the heartbeat), and difficulty breathing.

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

• Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.

• Cancers have been reported after treatment with Modigraf, including skin cancers and a rare type of cancer that may include skin lesions known as Kaposi's sarcoma. 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 the count of red blood cells), hemolytic anemia (a decrease in the number of red blood cells due to abnormal rupture accompanied by fatigue), and febrile neutropenia (a decrease in the type of white blood cells that fight infections, accompanied by fever). 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 sensation of coldness in your hands and feet.
• Agranulocytosis (a significant decrease in the number of white blood cells 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 onset of skin 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.
• Optic neuropathy (alteration of the optic nerve): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.Details

After receiving Modigraf, the following side effects may also occur and may be severe:

Very frequent 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.

Frequent 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 counts (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 electrolytes (see blood test).

-Anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders.

-Seizures, disorders of consciousness, tingling and numbness (sometimes painful) in the hands and feet, dizziness, decreased ability to write, nervous system disorders.

-Increased sensitivity to light, eye disorders.

-Tinnitus (ringing in the ears).

-Reduced blood flow in the 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, throat inflammation, cough, symptoms of a cold.

-Inflammatory or ulcerative conditions that cause abdominal pain or diarrhea, stomach bleeding, inflammatory or ulcerative conditions in the mouth, fluid accumulation in the intestines, 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.

-Pain in the joints, extremities, back, and feet, muscle spasms.

-Renal insufficiency, reduced urine production, urinary tract disorders or pain.

-General weakness, fever, fluid accumulation in the body, pain and discomfort, increased alkaline phosphatase in the blood, weight gain, altered sensation of temperature.

Poorly frequent 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, cardiac muscle disorders, increased heart muscle size, faster heartbeat, abnormal ECG, abnormal heart rate and pulse.

-Thrombosis of a vein in a limb, shock.

-Respiratory difficulties, respiratory tract disorders, asthma.

-Intestinal obstruction, increased blood levels of amylase, gastroesophageal reflux, delayed stomach emptying.

-Skin inflammation, sunburn sensation.

-Joint disorders.

-Urinary retention, painful menstruation, 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 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 pressure sensation, decreased mobility, ulcer.

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

-Muscle weakness.

-Abnormal echocardiogram.

-Liver insufficiency.

-Painful urination, blood in the urine.

-Increased body fat.

Children and adolescents

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

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side 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 and on the overwrap after “CAD”. The expiration date is the last day of the month indicated.

This medication does not require any special storage temperature.

After preparation, the suspension must be administered immediately.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. This will help protect the environment.

Modigraf Composition

• The active principle is tacrolimus.

Each Modigraf 0.2 mg granule contains 0.2 mg of tacrolimus (as monohydrate).

Each Modigraf 1 mg granule contains 1 mg of tacrolimus (as monohydrate).

• The other components are: lactose monohydrate, hypromellose (E464) and sodium croscarmellose (E468).

Appearance of the product and contents of the package

Modigraf oral suspension granules 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

Responsible for manufacturing

Astellas Ireland Co., Ltd.

Killorglin

County Kerry, V93FC86

Ireland

For further information about this medicinal product, please consult the representative of the marketing authorisation holder in your country:

Last update of this leaflet:

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