Modigraf 1 mg granules for oral suspension

Package leaflet: Information for the user

Introduction

Package leaflet: Information for the user

Modigraf 0.2 mg, granules for oral suspension

Modigraf 1 mg, granules for oral suspension

Tacrolimus

Read the entire leaflet carefully before you start taking this medicine, as 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 may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are adverse effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Modigraf is and what it is 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 attempt to reject the new organ. Modigraf is used to control your body's immune response, allowing you to accept the transplanted organ.

You may also be given Modigraf to treat ongoing rejection of your liver, kidney, heart, or other transplanted organ, or if any previous treatment you were receiving has failed to control this immune response following your transplant.

Modigraf is used in adults and children.

2. What you need to know before taking Modigraf

Do not take Modigraf

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

Warnings and precautions

Talk to your doctor or pharmacist before starting Modigraf

• 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 a disturbance in the electrical activity of your heart known as "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 fatigue, confusion, yellowing of the skin or eyes, reduced urine volume, vision loss, or seizures (see section 4). The risk of 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 Modigraf. 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 Modigraf.

You should maintain regular contact with your doctor. Periodically, your doctor may need to perform blood and urine tests, cardiac tests, and eye examinations to determine the appropriate dose of Modigraf.

You should limit your exposure to sunlight and UV (ultraviolet) radiation while taking Modigraf. This is because immunosuppressants such as Modigraf may increase the risk of skin cancer. When exposed to sunlight, 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, and avoid breathing near them. If such contact occurs, wash the skin and eyes thoroughly.

Other medicines and Modigraf

Inform your doctor or pharmacist if you are currently taking, have recently taken, or might need to take any other medicines.

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

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

• antifungals and antibiotics, especially macrolide antibiotics used to treat infections, e.g., ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid, and flucloxacillin
• letermovir, used to prevent diseases caused by CMV (human cytomegalovirus)
• HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), the booster drug 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, ombitasvir/paritaprevir/ritonavir combination, 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-aluminum hydroxide, used to treat heartburn
• oral contraceptives, hormonal treatments containing 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 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 other things, to treat 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 Modigraf after starting hepatitis C treatment.

Inform your doctor if you are taking 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 Modigraf.

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

If you plan to get vaccinated, consult your doctor.

Taking 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 could potentially affect your baby's health or harm the course of pregnancy.

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before using this medicine. One 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, occurring 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 Modigraf was found. Modigraf passes into breast milk. Therefore, you must not breastfeed while taking Modigraf.

Driving and using machines

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

Modigraf contains lactose and sodium

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

This medicine contains less than 1 mmol of sodium (23 mg) per sachet; hence, it is essentially "sodium-free".

3. How to take Modigraf

Follow exactly the administration instructions for this medicine as given by your doctor. If in doubt, consult your doctor or pharmacist again. Modigraf should be prescribed by physicians experienced in the treatment of 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 switch to a different tacrolimus medicine.

This medicine must be taken twice daily. If the physical appearance has changed from the normal white granules, 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. Initial doses immediately after transplantation are generally within the range of 0.075 – 0.30 mg per kg of body weight per day, depending on the transplanted organ. For treatment of rejection, the same dose may be used.

Your dose depends on your general 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 require higher doses per kg of body weight than adults to achieve the same effective blood levels.

After starting 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 reduce your Modigraf dose once your condition has stabilized. Your doctor will tell you exactly how many sachets to take.

You will need to take Modigraf every day for as long as you require immunosuppression to prevent rejection of your transplanted organ. You should maintain regular contact with your doctor.

Modigraf is taken orally twice daily, 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 before 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 water volume accurately, you may 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 water on a stable surface. Do not use cups or spoons made of PVC (polyvinyl chloride) to prepare Modigraf, as the active substance in Modigraf may adhere to PVC.

Carefully open the prescribed number of sachets, for example, with scissors at the point indicated by an arrow. Hold the opened sachet between your thumb and index finger above the cup, with the open side of the sachet facing downwards. 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 obtain the correct amount of granules from the sachet. It is normal for some granules to remain inside; the sachet is designed this way.

Gently shake or stir until the granules are completely suspended. The suspension can be drawn up with a syringe or the patient may drink it directly. The liquid has a sweet taste. Rinse the glass or cup once with the same amount of water and drink this as well. The liquid should be taken 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 make up for missed individual doses.

If you forget 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 do so.

If you have any further questions about 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 everyone will experience them.

Modigraf reduces your body's defence mechanisms (immune system), which will therefore not work as effectively in fighting infections. As a result, if you are taking Modigraf, you will be more likely to develop 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 rare and serious brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML)

Serious effects may occur, including allergic and anaphylactic reactions (a very severe type of allergic reaction with fainting and difficulty breathing, requiring immediate medical attention). Benign and malignant tumours have been reported after treatment with Modigraf.

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 haemolytic uraemic syndrome, with the following symptoms: low or no urine output (acute kidney failure), extreme tiredness, yellowing of the skin or eyes (jaundice), and bruising or abnormal bleeding, and signs of infection.

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

• Thrombotic thrombocytopenic purpura: includes damage to the smallest blood vessels and is characterised 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), loss of vision, 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, severe illness with blistering of the skin, mouth, eyes, and genitals, hives, tongue swelling, red or purple rash that spreads, 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), fainting, dizziness or nausea, palpitations (awareness of heartbeats), and difficulty breathing.

Serious adverse effects with unknown frequency (frequency cannot be estimated from available data):

• Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhoea, fever, and sore throat.
• Benign and malignant tumours have been reported after treatment as a result of immunosuppression, including malignant skin cancers and a rare type of cancer that may involve skin lesions known as Kaposi's sarcoma. Symptoms include skin changes such as new discolourations or changes in existing ones, lesions, or lumps.
• Cases of pure red cell aplasia (a very marked reduction in red blood cell count), haemolytic anaemia (reduction 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 you may feel 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 colour vision, difficulty seeing details, or reduced visual field.

After receiving Modigraf, 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.
• Abnormal liver function tests.
• Diarrhoea, 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 consciousness level, 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 the heart 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, throat inflammation, cough, flu-like symptoms.
• Inflammations or ulcers causing abdominal pain or diarrhoea, stomach bleeding, mouth ulcers or inflammation, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, abdominal 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, urinary disorders 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 blood proteins or sugar, increased blood phosphate.
• Coma, brain haemorrhage, stroke, paralysis, brain disorders, speech and language abnormalities, memory problems.
• Lens opacity.
• 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 amylase enzyme level, 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, flu-like 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 bleedings due to blood clots.
• Increased muscle stiffness.
• Deafness.
• Fluid accumulation around the heart.
• Acute shortness of breath.
• Cyst formation in the pancreas.
• Problems with blood flow in the liver.
• Increased hairiness.
• 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.

Children and adolescents

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

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 Modigraf

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

Do not use this medicine after the expiry date stated on the packaging and sachet after "EXP". The expiry date refers to 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 must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Modigraf

• The active substance is tacrolimus.

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

Each Modigraf 1 mg granule sachet 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 pack

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

Packs of 50 sachets are available.

Marketing Authorization Holder

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

The Netherlands

Manufacturer

Astellas Ireland Co., Ltd.

Killorglin

County Kerry, V93FC86

Ireland

More information about this medicinal product is available upon request from the local representative of the Marketing Authorization Holder:

Date of the most recent review of this leaflet:

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