PROGRAF 5 mg/ml CONCENTRATE FOR INFUSION SOLUTION

2. What you need to know before you use Prograf

Do not use Prograf

• If you are allergic (hypersensitive) to tacrolimus or to any macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin).
• If you are allergic (hypersensitive) to any of the other ingredients of Prograf (listed in section 6), especially hydrogenated castor oil or similar substances.

Warnings and Precautions

Consult your doctor, pharmacist, or nurse before starting Prograf

• While you are receiving Prograf, your doctor may want to perform occasional tests (including blood tests, urine tests, heart function tests, visual tests, and neurological tests). This is completely normal and will help your doctor decide on the most suitable dose of Prograf for you.
• Please avoid taking any herbal preparations, e.g. St. John's Wort (Hypericum perforatum) or any other herbal products, as this may affect the effectiveness and dose of Prograf you need to receive. If you are in doubt, please consult your doctor before taking any herbal products or preparations.
• If you have liver problems or have had a disease that may have affected your liver, please inform your doctor, as this may affect the dose of Prograf you receive.
• If you experience severe abdominal pain accompanied by other symptoms such as chills, fever, nausea, or vomiting.
• If you have diarrhea for more than a day, please inform your doctor, as it may be necessary to adjust the dose of Prograf you receive.
• If you have a heart condition called "QT interval prolongation".
• Limit your exposure to sunlight and UV light while taking Prograf by using protective clothing and sunscreen with a high sun protection factor. This is due to the potential risk of malignant skin changes with immunosuppressive therapy.
• If you need to be vaccinated, please inform your doctor beforehand. He will advise you on the best course of action.
• It has been reported that some patients treated with Prograf have an increased risk of developing lymphoproliferative disorders (see section 4). Ask your doctor for more information about these disorders.
• If you have or have had small blood vessel damage, known as thrombotic microangiopathy/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, 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.

Handling precautions:

During preparation, avoid contact of any part of the body, such as skin or eyes, as well as inhaling near the solutions for injection, powder, or granules contained in tacrolimus products. If such contact occurs, wash the skin and eyes.

Other Medicines and Prograf

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

Prograf must not be used with cyclosporin.

If you need to visit a different doctor from your transplant specialist, tell the doctor that you are taking tacrolimus. Your doctor may need to consult your transplant specialist if you need to use another medicine that may increase or decrease your blood level of tacrolimus.

The blood levels of Prograf may be altered by other medicines you are taking, and the blood levels of other medicines may be altered by the administration of Prograf, which may require interruption, increase, or decrease of the dose of Prograf. Some patients have experienced increased blood levels of tacrolimus while taking other medicines. This could lead to serious side effects, such as kidney problems, nervous system problems, and heart rhythm disorders (see section 4).

The effect on Prograf blood levels may occur soon after starting to use another medicine, so it may be necessary to monitor the blood level of Prograf frequently and continuously during the first few 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 may increase the risk of organ rejection. In particular, you should inform your doctor if you are taking or have recently taken medicines with active ingredients 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 (efavirenz, etravirine, nevirapine) used to treat HIV infections
• HCV protease inhibitors (e.g. telaprevir, boceprevir, the combination ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, elbasvir/grazoprevir, and glecaprevir/pibrentasvir), used to treat hepatitis C infection
• nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane (used to treat certain types of cancer)
• mycophenolic acid, used to suppress the immune system as a prevention of transplant rejection
• medicines for stomach ulcers and acid reflux (e.g. omeprazole, lansoprazole, or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
• magnesium-aluminum hydroxide (antacid), used to treat acidity
• hormonal treatments with ethinylestradiol (e.g. the "pill" oral contraceptive) or danazol
• medicines used to treat high blood pressure or heart problems, such as 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
• antiepileptic medicines carbamazepine, phenytoin, or phenobarbital
• metamizole, used to treat pain and fever
• corticosteroids prednisone and methylprednisolone
• the antidepressant nefazodone
• herbal medicines containing St. John's Wort (Hypericum perforatum) or extracts of Schisandra sphenanthera
• cannabidiol (its use includes, among others, the treatment of epileptic seizures).

Inform your doctor if you are receiving treatment for hepatitis C. The pharmacological treatment for hepatitis C may change your liver function and may affect the 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 the blood levels of tacrolimus and make necessary adjustments to the dose of Prograf after starting treatment for hepatitis C.

Inform your doctor if you are taking or need to take ibuprofen, amphotericin B, antibiotics (cotrimoxazole, vancomycin, or aminoglycoside antibiotics such as gentamicin), or antivirals (e.g. aciclovir, ganciclovir, cidofovir, foscarnet). These medicines may worsen kidney or nervous system problems when taken with Prograf.

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

Your doctor also needs to know if you are taking potassium supplements or potassium-sparing diuretics (e.g. amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim and cotrimoxazole, which may increase potassium levels in your blood, some painkillers (so-called NSAIDs, e.g. ibuprofen), anticoagulants, or oral medication for diabetic treatment, while you are receiving Prograf.

If you need to be vaccinated, please inform your doctor beforehand.

Using Prograf with Food and Drink

Grapefruit or grapefruit juice should be avoided while receiving Prograf.

Pregnancy and Breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using 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 developed during pregnancy or the postpartum period (a condition called preeclampsia). No increased risk of serious congenital anomalies associated with the use of Prograf was found.

Prograf passes into breast milk. Therefore, you should not breastfeed while receiving Prograf.

Prograf Contains Hydrogenated Castor Oil and Ethanol

• Prograf contains hydrogenated castor oil, which may, in a small number of patients, cause a severe allergic reaction. If you have had this problem before, please inform your doctor.
• This medicine contains 81% ethanol (alcohol), which corresponds to an amount of 638 mg per milliliter, equivalent to 16 ml of beer, 7 ml of wine. The small amount of alcohol in this medicine does not produce any noticeable effect.

3. How to Use Prograf

The initial dose to prevent rejection of your transplanted organ will be determined by your doctor based on your body weight. The initial intravenous dose immediately after transplantation will generally be within the range of

0.01-0.10 mg per kg body weight and per day

depending on your transplanted organ.

Prograf will only be used for intravenous infusion once diluted. You will receive Prograf as a continuous infusion over 24 hours and never as a short injection.

Prograf may cause moderate irritation if not administered directly into a vein.

Treatment with Prograf should not be prolonged for more than 7 days. Then your doctor will prescribe Prograf capsules instead.

Your dose depends on your general condition and any other immunosuppressive medication you may be taking. Your doctor will need to perform regular blood tests to determine the correct dose and to adjust the dose from time to time.

If you use more Prograf than you should

If you have received too much Prograf, your doctor will correct the next dose.

If you stop treatment with Prograf

Stopping your treatment with Prograf 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.

Prograf reduces the body's defense mechanism that allows it to reject the transplanted organ. Consequently, the body will not function as well as usual in fighting infections. Therefore, if you are taking Prograf, you will be more prone than usual to suffer from infections, such as skin, mouth, stomach, and intestinal infections, lung and urinary tract 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 of weakness or general malaise
• Memory loss, thinking problems, difficulty walking, or vision loss – these symptoms may be due to a rare and severe brain infection (progressive multifocal leukoencephalopathy or PML)

Severe adverse effects may occur, including those listed below.

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

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

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

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

• Thrombotic thrombocytopenic purpura: includes lesions in small 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), vision loss, 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 severe adverse effects (may affect up to 1 in 10,000 people):

• Stevens-Johnson syndrome: unexplained generalized skin pain, facial swelling, severe disease with blistering of the skin, mouth, eyes, and genitals, hives, swelling of the tongue, red or purple 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 bumps.
• 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 feel sudden fever, chills, and sore throat.
• Allergic and anaphylactic reactions with symptoms such as sudden itchy 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 (damage to the optic nerve): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.

The following adverse effects may also occur after receiving Prograf and may be severe:

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 cell count (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell count (see blood test)
• Decreased 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
• Symptoms of anxiety, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders
• Seizures, changes in consciousness, tingling and numbness (sometimes painful) of hands and feet, dizziness, difficulty writing, changes in the nervous system
• Increased sensitivity to light, eye changes
• Hearing sounds in the ears
• Decreased blood flow in the heart vessels, faster heart rate
• Bleeding, partial or complete blockage of blood vessels, decreased blood pressure
• Difficulty breathing, changes in the respiratory tract, asthma
• Intestinal obstruction, increased blood level of the enzyme amylase, reflux of stomach contents into the throat, delayed emptying of the stomach
• Dermatitis, sensation of burning under sunlight
• Joint disorders
• Difficulty urinating, painful and abnormal menstrual bleeding
• Failure of some organs, flu-like illness, increased sensitivity to heat and cold, feeling of pressure in the chest, nervousness or strange feeling, increased lactate dehydrogenase enzyme in the blood, weight loss

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

• Changes in blood coagulation, decrease in all blood cell counts
• Dehydration
• Decreased protein or sugar in the blood, increased phosphate in the blood
• Coma, cerebral hemorrhage, stroke, paralysis, brain disorder, changes in speech and language, memory problems
• Cataract
• Difficulty hearing
• Irregular heartbeat, cardiac arrest, decreased heart function, changes in the heart muscle, increased heart muscle, stronger heartbeat, abnormal electrocardiogram, abnormal heart rate and pulse
• Blood clots in a limb vein, shock
• Breathing difficulties, changes in the respiratory tract, asthma
• Intestinal obstruction, increased blood level of the enzyme amylase, reflux of stomach contents into the throat, delayed emptying of the stomach
• Dermatitis, sensation of burning under sunlight
• Joint disorders
• Difficulty urinating, painful and abnormal menstrual bleeding
• Failure of some organs, flu-like illness, increased sensitivity to heat and cold, feeling of pressure in the chest, nervousness or strange feeling, increased lactate dehydrogenase enzyme in the blood, weight loss

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

• Small bleeding spots on the skin due to blood clots
• Increased muscle stiffness
• Deafness
• Fluid accumulation around the heart
• Acute difficulty breathing
• Formation of cysts in the pancreas
• Problems with blood flow in the liver
• Increased hair growth
• Thirst, falls, feeling of pressure in the chest, decreased mobility, ulcers

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

• Muscle weakness
• Abnormal echocardiogram
• Liver failure, narrowing of the bile duct
• Painful urination with blood in the urine
• Increased fatty tissue

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 is not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Prograf

Keep out of sight and reach of children.

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

Store the ampoule in the original packaging to protect it from light.

Do not store above 25°C.

6. Package Contents and Additional Information

Composition of Prograf

• The active ingredient is tacrolimus. 1 ml of concentrate for solution for infusion contains 5 mg.
• The other ingredients are hydrogenated and polyoxyethylated castor oil and anhydrous ethanol.

Appearance of the Product and Package Contents

The concentrate is a clear, colorless solution presented in transparent glass ampoules. Each ampoule contains 1 ml of concentrate for solution for infusion, which must be diluted before use.

Each box contains 10 ampoules.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Astellas Pharma, S.A.

Paseo de la Castellana, 259 D - Planta 31

28046 Madrid (Spain)

Manufacturer:

Astellas Ireland Co. Limited

Killorglin, County Kerry, V93FC86

Ireland

This Medicine is Authorized in the Member States of the European Economic Area under the Following Names:

Prograf:

Austria, Cyprus, Czech Republic, Denmark, Germany, Greece, Spain, Finland, France, Hungary, Ireland, Iceland, Italy, Malta, Norway, Poland, Portugal, Slovakia, Slovenia, Sweden.

Prograft:

Belgium, Luxembourg, Netherlands.

Date of the Last Revision of this Leaflet: February 2025

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended only for doctors or healthcare professionals:

• Prograf 5 mg/ml concentrate for solution for infusion should not be injected undiluted.
• Prograf 5 mg/ml concentrate for solution for infusion must be diluted in a 5% w/v dextrose solution or in physiological saline solution, in polyethylene, polypropylene, or glass bottles, but not in PVC containers. Only clear and colorless solutions should be used.
• The concentration of the infusion solution should be between 0.004 and 0.100 mg/ml. The total infusion volume over a 24-hour period should be 20-500 ml.
• The diluted solution should not be administered as a bolus.
• The infusion solution should be used within 24 hours.

The unused concentrate in an opened ampoule or the unused reconstituted solution should be discarded immediately to avoid contamination.