Prograf

Leaflet accompanying the packaging: patient information

Prograf, 5 mg/ml, concentrate for solution for infusion

Tacrolimus

Read the leaflet carefully before taking the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, please tell your doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

• 1. What is Prograf and what is it used for
• 2. Important information before taking Prograf
• 3. How to take Prograf
• 4. Possible side effects
• 5. How to store Prograf
• 6. Contents of the pack and other information

1. What is Prograf and what is it used for

Prograf belongs to a group of medicines called immunosuppressants. After organ transplantation (e.g. liver, kidney, or heart), the patient's immune system will try to reject the new organ. Prograf is used to control the immune system's response and allow the transplanted organ to be accepted. Prograf is often used in combination with other medicines that also suppress the immune system. Prograf may also be used in cases of rejection of a transplanted liver, kidney, heart, or other organ, or if previous treatment did not control the immune system's response after organ transplantation.

2. Important information before taking Prograf

When not to take Prograf

• If you are allergic (hypersensitive) to tacrolimus or any other 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 polyoxyethylated hydrogenated castor oil or a similar substance.

Warnings and precautions

Before starting treatment with Prograf, discuss it with your doctor or pharmacist.

• If you are taking Prograf, your doctor may order regular tests (blood tests, urine tests, heart function tests, vision tests, and neurological tests). These are routine tests that will help determine the correct dose of Prograf.
• You should avoid taking herbal preparations containing St. John's Wort (Hypericum perforatum) and other herbal preparations, as they may affect the efficacy and dose of Prograf that you need to take. If in doubt, consult your doctor before taking any herbal preparations.

and

• If you have liver function disorders or have had them in the past, you should inform your doctor, as these conditions may affect the dose of Prograf.
• If you experience severe abdominal pain with or without other symptoms such as chills, fever, nausea, or vomiting.
• If you experience diarrhea lasting more than one day, you should inform your doctor, as it may be necessary to adjust the dose of Prograf.
• If you experience a change in the electrical activity of the heart called "QT interval prolongation".
• You should limit exposure to sunlight and ultraviolet radiation, wearing protective clothing and using sunscreens with a high protection factor. This is related to the risk of developing malignant skin changes during immunosuppressive treatment.
• If you are going to receive a vaccine, you should inform your doctor. Your doctor will advise on the best course of action.
• In patients treated with Prograf, an increased risk of lymphoproliferative disorders has been observed (see section 4). You should ask your doctor for specific advice on these disorders.
• If you experience or have experienced damage to the smallest blood vessels, known as microangiopathy thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. You should inform your doctor if you experience: fever, bruising under the skin (which may look like red spots), unexplained fatigue, confusion, yellowing of the skin or eyes, decreased urine output, loss of vision, and seizures (see section 4). If you take tacrolimus with sirolimus or everolimus, the risk of these symptoms may increase. Precautions for preparing the medicine: When preparing, avoid direct contact with any part of the body, such as skin or eyes, or inhaling products containing tacrolimus in the form of a solution, powder, or granules. If such contact occurs, wash the skin and eyes.

Prograf and other medicines

Tell your doctor or pharmacist about all medicines you are taking now or have recently taken, as well as any medicines you plan to take, including over-the-counter medicines and herbal preparations.

Do not take Prograf with cyclosporin.

If you need to visit a doctor other than a transplant specialist, tell the doctor that you are taking tacrolimus. The doctor may want to consult with a transplant specialist to determine if you should take a different medicine that may increase or

decrease the level of tacrolimus in your blood.The level of Prograf in your blood may change when taking other medicines, and the level of other medicines in your blood may change when taking Prograf. Taking these medicines may require stopping treatment, increasing, or decreasing the dose of Prograf. In some patients, an increase in tacrolimus levels in the blood has been observed when taking other medicines. This could lead to serious side effects, such as kidney function disorders, nervous system disorders, and heart rhythm disorders (see section 4). The effect on Prograf levels in the blood can occur very quickly after starting another medicine, so it may be necessary to frequently monitor Prograf levels in the blood during the first few days after starting another medicine and during continued treatment with another medicine. Some other medicines may cause a decrease in tacrolimus levels in the blood, which could increase the risk of rejecting the transplanted organ. In particular, you should tell your doctor about any medicines you are currently taking or have recently taken, containing active substances such as:

• antifungal medicines 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 cytomegalovirus (CMV) disease
• HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), a medicine that increases the pharmacokinetics of cobicistat, and tablets or non-nucleoside reverse transcriptase inhibitors (efavirenz, etravirine, nevirapine) used to treat HIV infection
• HCV protease inhibitors (e.g. telaprevir, boceprevir, ombitasvir/paritaprevir/ritonavir in combination with dasabuvir or without it, elbasvir/grazoprevir, and glecaprevir/pibrentasvir) used to treat hepatitis C
• nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane (used to treat certain cancers)
• mycophenolic acid, used to suppress the immune system to prevent transplant rejection
• medicines used to treat stomach ulcers and acid reflux (e.g. omeprazol, lansoprazole, or cimetidine)
• antiemetic medicines used to treat nausea and vomiting (e.g. metoclopramide)
• medicines containing aluminum or magnesium hydroxide (which neutralize stomach acid), used to treat heartburn
• hormonal medicines containing ethinyl estradiol (e.g. oral contraceptives) or danazol
• medicines used to treat high blood pressure or heart disease, such as nifedipine, nicardipine, diltiazem, and verapamil
• antiarrhythmic medicines (amiodarone) used to control heart rhythm disorders (irregular heartbeat)
• medicines known as "statins" used to treat high cholesterol and triglycerides
• antiepileptic medicines, e.g. carbamazepine, phenytoin, or phenobarbital
• metamizole, used to treat pain and fever
• corticosteroids prednisolone and methylprednisolone
• antidepressant nefazodone
• herbal products containing St. John's Wort (Hypericum perforatum) or Schisandra sphenanthera extract
• cannabidiol (used, among other things, to treat seizures). You should tell your doctor if you are being treated for hepatitis C. Treatment of hepatitis C may change liver function and may affect tacrolimus levels in the blood. Tacrolimus levels in the blood may decrease or increase depending on the medicines prescribed for hepatitis C. Your doctor may want to closely monitor tacrolimus levels in the blood and make necessary dose changes after starting hepatitis C treatment. You should tell your doctor if you are taking or plan to take ibuprofen, amphotericin B, antibiotics (cotrimoxazole, vancomycin, or aminoglycoside antibiotics such as gentamicin), or antiviral medicines (e.g. acyclovir, ganciclovir, cidofovir, or foscarnet). These medicines taken with Prograf may increase the risk of kidney function disorders and nervous system disorders. You should inform your doctor about taking sirolimus or everolimus. If you take tacrolimus with sirolimus or everolimus, the risk of developing thrombotic microangiopathy, thrombocytopenic purpura, and hemolytic uremic syndrome may increase (see section 4). You should tell your doctor if you are taking potassium or using potassium-sparing diuretics (e.g. amiloride, triamterene, or spironolactone) or antibiotics trimethoprim or cotrimoxazole, which may increase potassium levels in the blood,

and

• certain painkillers (non-steroidal anti-inflammatory drugs, e.g. ibuprofen), anticoagulants, or oral antidiabetic medicines.

Taking Prograf with food and drink

Avoid eating grapefruits and drinking grapefruit juice while taking Prograf.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a baby, ask your doctor or pharmacist for advice before taking this medicine. In one study, the course of pregnancy was evaluated in women treated with tacrolimus and in women treated with other immunosuppressive medicines. The study did not provide sufficient data to draw conclusions, but a higher frequency of miscarriages was observed in patients with liver and kidney transplants treated with tacrolimus, as well as a higher frequency of persistent hypertension associated with proteinuria, which develops during pregnancy or postpartum (pre-eclampsia). No increased risk of serious birth defects associated with Prograf has been demonstrated. Prograf passes into breast milk. Therefore, do not breastfeed while taking Prograf.

Prograf contains polyoxyethylated hydrogenated castor oil and ethanol

• -Prograf contains polyoxyethylated hydrogenated castor oil, which may cause severe allergic reactions in a small number of patients. You should tell your doctor if you have had such reactions in the past.
• -Prograf 5 mg/ml concentrate for solution for infusion contains 81% v/v ethanol (alcohol), i.e. 638 mg per dose, which is equivalent to 16 ml of beer or 7 ml of wine per dose. The small amount of alcohol in this medicine will not cause any noticeable effects.

3. How to take Prograf

Your doctor will determine the initial dose to prevent rejection of the transplanted organ based on your body weight. The usual initial dose of Prograf given immediately after transplantation depends on the type of transplanted organ and is usually between 0.01 mg/kg body weight/day and 0.10 mg/kg body weight/day. The concentrate must be used for intravenous infusions only after prior dilution. Prograf will be administered in a continuous intravenous infusion lasting 24 hours, never as a rapid intravenous injection. Prograf may cause mild irritation if not administered directly into a vein. Treatment should not last longer than 7 days. Then, your doctor will advise you to continue treatment orally, prescribing Prograf in capsule form. The dose also depends on your overall health and other immunosuppressive medicines you are taking. To determine the correct dose and modify it during treatment, your doctor will order regular blood tests.

Taking a higher dose of Prograf than recommended

If a higher dose of Prograf is taken, your doctor will change the dose of the next administration.

Stopping treatment with Prograf

Stopping treatment with Prograf may increase the risk of rejecting the transplanted organ. Do not stop treatment unless your doctor decides to do so. If you have any further questions about taking this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Prograf can cause side effects, although not everybody gets them. Prograf weakens the body's defense mechanism to prevent rejection of the transplanted organ. As a result, the body's ability to fight infections is reduced. Therefore, while taking Prograf, you are more susceptible to infections than usual, such as skin, mouth, stomach, and intestinal infections, lung and urinary tract infections. Some infections can be severe or life-threatening and may include bacterial, viral, fungal, parasitic, or other infections. You should immediately inform your doctor if you experience symptoms of infection, including:

• fever, cough, sore throat, weakness, or general malaise
• memory loss, difficulty thinking, difficulty walking, or loss of vision - these may be caused by a very rare, serious brain infection that can be life-threatening (progressive multifocal leukoencephalopathy, PML).

Severe side effects may occur, including those listed below.

If you experience or suspect that you have experienced any of the following severe side effects, tell your doctor immediately:

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

• perforation of the gastrointestinal tract: severe abdominal pain, which may be accompanied by other symptoms such as chills, fever, nausea, or vomiting
• disorders of the transplanted organ
• blurred vision

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

• thrombotic microangiopathy (damage to the smallest blood vessels), including hemolytic uremic syndrome, with symptoms such as: little or no urine output, extreme fatigue, yellowing of the skin or eyes (jaundice), and unexplained bruising or bleeding
• thrombocytopenic purpura: a condition characterized by damage to the smallest blood vessels and symptoms such as fever and bruising under the skin (which may look like red spots) with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), and symptoms of acute kidney failure (little or no urine output), loss of vision, and seizures

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

• Stevens-Johnson syndrome: unexplained, widespread skin pain, facial swelling, severe illness, with blisters on the skin, mouth, eyes, and genitals, hives, swelling of the tongue, and a spreading red or purple rash on the skin

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

• Torsades de pointes: a change in heart rate, which may be accompanied by symptoms such as chest pain (angina pectoris), fainting, dizziness, or nausea, palpitations (feeling of heartbeat), and difficulty breathing

Frequency not known (frequency cannot be estimated from the available data):

• opportunistic infections (bacterial, fungal, viral, and parasitic): prolonged diarrhea, fever, and sore throat
• benign and malignant tumors that occur during immunosuppression, including skin cancer and a rare type of cancer that may appear as skin changes, called Kaposi's sarcoma. Symptoms include skin changes, such as new or changed pigmentation, spots, or bumps.
• pure red cell aplasia (a significant decrease in the number of red blood cells), hemolytic anemia (a decrease in the number of red blood cells due to abnormal breakdown, accompanied by fatigue), and febrile neutropenia (a decrease in the number of white blood cells that fight infections, with a fever). The exact frequency of these side effects is unknown. You may not have any symptoms or, depending on the severity of the disease, you may feel tired, apathetic, unusually pale (pallor), short of breath, dizzy, headache, chest pain, and cold hands and feet.
• agranulocytosis (a significant decrease in the number of white blood cells, with mouth ulcers, fever, and infection/infections). You may not have any symptoms or you may feel a sudden increase in body temperature, chills, and sore throat.
• allergic and anaphylactic reactions with symptoms such as: sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and a feeling of impending fainting
• posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood changes, seizures, and blurred vision. These may be symptoms of a condition known as posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.

Other side effects that may occur when taking Prograf:

Very common side effects (may affect more than 1 in 10 people):

• increased blood sugar levels, diabetes, increased potassium levels in the blood
• insomnia
• muscle tremors, headache
• high blood pressure
• abnormal liver function tests
• diarrhea, nausea
• kidney function disorders

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

• decrease in blood cell count (platelets, red blood cells, or white blood cells), increase in white blood cell count, change in red blood cell count (visible in blood tests)
• decrease in magnesium, phosphorus, potassium, calcium, or sodium levels in the blood, fluid retention in the body, increase in uric acid or fat levels in the blood, decrease in appetite, increase in blood acidity, other electrolyte disorders
• anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, and psychiatric disorders
• seizures, impaired consciousness, tingling and numbness (sometimes painful) of the hands and feet, dizziness, impaired writing ability, and nervous system disorders
• increased sensitivity to light, eye disorders
• ringing in the ears
• decreased blood flow in the heart's blood vessels, rapid heartbeat
• bleeding, partial or complete blockage of blood vessels, decreased blood pressure
• shortness of breath, changes in lung tissue, fluid accumulation in the pleura, inflammation of the throat, cough, and flu-like symptoms
• inflammatory or ulcerative conditions causing abdominal pain or diarrhea, gastrointestinal bleeding, mouth ulcers, fluid accumulation in the abdominal cavity, vomiting, abdominal pain, indigestion, constipation, bloating and gas, bloating, and gas
• abnormal liver enzyme tests and liver function disorders, yellowing of the skin due to liver disorders, liver cell damage, and liver inflammation
• itching, rash, hair loss, acne, excessive sweating
• joint pain, limb pain, back pain, and foot pain, muscle cramps
• kidney failure, decreased urine output, painful or difficult urination
• general weakness, fever, fluid retention in the body, pain, and discomfort, increased activity of the enzyme lactate dehydrogenase in the blood, weight gain, and disorders of temperature perception

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

• changes in blood clotting and bleeding parameters, decrease in all types of blood cells
• dehydration
• decrease in blood protein or sugar levels, increase in phosphate levels in the blood
• coma, brain bleeding, stroke, paralysis, and paresis, brain disorders, speech disorders, and language disorders
• cataract
• hearing disorders
• irregular heartbeat, cardiac arrest, heart failure, heart muscle disorders, heart enlargement, increased heart rate, abnormal ECG results, and abnormal heart rate and rhythm
• blood clots in the veins of the limbs, shock
• breathing difficulties, respiratory system disorders, asthma
• intestinal obstruction, increased amylase enzyme activity in the blood, gastroesophageal reflux, delayed gastric emptying
• skin inflammation, increased sensitivity to sunlight
• joint disorders
• inability to urinate, painful menstruation, and abnormal menstrual bleeding
• organ failure, flu-like symptoms, increased sensitivity to heat and cold, feeling of pressure in the chest, irritability, or malaise, increased activity of the enzyme lactate dehydrogenase in the blood, weight loss

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

• small, bloody spots on the skin due to blood clots
• increased muscle tension
• deafness
• fluid accumulation around the heart
• severe shortness of breath
• pancreatic cyst
• impaired blood flow through the liver
• excessive hair growth
• thirst, falls, feeling of pressure in the chest, decreased mobility, and ulcers

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

• muscle weakness
• abnormal echocardiogram
• liver failure, narrowing of the bile ducts
• painful urination with blood
• increased amount of fatty tissue

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, please tell your doctor. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocidal Products, Jerozolimskie Avenue 181C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl. Side effects can also be reported to the marketing authorization holder. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Prograf

Keep Prograf out of the sight and reach of children. Do not use Prograf after the expiry date stated on the carton and ampoule after {EXP.}. The expiry date refers to the last day of the month stated. Store in the original packaging to protect from light. Do not store above 25°C.

6. Contents of the pack and other information

What Prograf contains

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

What Prograf looks like and contents of the pack

The concentrate is a colorless, clear solution available in a colorless glass type I ampoule. Each ampoule contains 1 ml of the concentrate for solution for infusion, which must be diluted before administration. Each carton contains 10 ampoules.

Marketing authorization holder and manufacturer

Marketing authorization holder: Astellas Pharma Sp. z o.o., Żwirki i Wigury 16C, 02-092 Warsaw, Tel.: (22) 545 11 11. Manufacturer: Astellas Ireland Co., Ltd., Killorglin, County Kerry V93FC86, Ireland.

This medicinal product 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, Iceland, Ireland, Italy, Malta, Norway, Poland, Portugal, Slovakia, Slovenia, Sweden. Prograft: Belgium, Luxembourg, Netherlands.

Date of last revision of the leaflet: 02/2025

-----------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Prograf 5 mg/ml concentrate for solution for infusion should not be administered without dilution. Prograf 5 mg/ml concentrate for solution for infusion should be diluted in 5% glucose solution or 0.9% sodium chloride solution in containers made of polyethylene, polypropylene, or glass, but not in PVC containers. Only clear and colorless solutions should be administered. The concentration of the prepared infusion solution should be between 0.004 mg/ml and 0.1 mg/ml. The total volume of the infusion solution for administration in a 24-hour intravenous infusion should be between 20 ml and 500 ml. The diluted solution should not be administered as a rapid intravenous injection (bolus). The diluted solution should be used within 24 hours. Unused concentrate from an opened ampoule or unused solution should be discarded immediately to avoid contamination.