Package leaflet: Information for the patient

Prograf, 5 mg/ml, concentrate for solution for infusion
Tacrolimus
Please read all of this leaflet carefully before using this medicine, because it contains
important information for you.

Keep this leaflet, as you may need to read it again.
If you have any further questions, please ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm other people, even if their symptoms are the same.
If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

What Prograf is and what it is used for
What you need to know before using Prograf
How to use Prograf
Possible side effects
How to store Prograf
Contents of the pack and other information

1. What Prograf is and what it is used for

Prograf belongs to a group of medicines called immunosuppressants. After an organ transplant (e.g. liver, kidney, or heart), the patient's immune system may try to reject the transplanted organ. Prograf is used to control the body's immune response and to help the body accept the transplanted organ.
Prograf is often used together with other medicines that also suppress the immune system.
Prograf may also be used to treat rejection of a transplanted liver, kidney, heart, or other organ, or when previous treatment has not controlled the immune response following organ transplantation.

2. Important information before using Prograf

When not to use Prograf

If the patient is allergic (hypersensitive) to tacrolimus or to any macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin).
If the patient is allergic (hypersensitive) to any of the other ingredients of Prograf (listed in section 6), particularly to hydrogenated castor oil polyoxyl or a similar substance.

Warnings and precautions
Before starting treatment with Prograf, discuss this with your doctor or pharmacist.

Your doctor may prescribe periodic check-ups (blood tests, urine tests, heart function tests, eye examinations, and neurological examinations). These are routine tests that help determine the appropriate dose of Prograf.
Avoid using herbal products containing St. John’s wort (Hypericum perforatum) and other herbal remedies, as they may affect the effectiveness and required dose of Prograf. If in doubt, consult your doctor before using any herbal products.
Inform your doctor if you have or have had liver function disorders, as these conditions may affect the required dose of Prograf.
If you experience severe abdominal pain, with or without other symptoms such as chills, fever, nausea, or vomiting.
If you develop diarrhea lasting longer than one day, inform your doctor, as it may be necessary to adjust your dose of Prograf.
If you have a change in the electrical activity of the heart known as "QT interval prolongation."
Limit exposure to sunlight and ultraviolet radiation by wearing protective clothing and using high-protection sunscreens. This is due to the risk of developing skin malignancies during immunosuppressive therapy.
If you are due to receive a vaccine, inform your doctor beforehand. Your doctor will advise on the best course of action.
Patients treated with Prograf have shown an increased risk of lymphoproliferative disorders (see section 4). Please consult your doctor for specific advice regarding these disorders.
Inform your doctor if you have or have had damage to the smallest blood vessels, known as thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome. Inform your doctor if you experience: fever, skin bruising (which may appear as red spots), unexplained fatigue, confusion, yellowing of the skin or eyes, reduced urine output, vision loss, or seizures (see section 4). The risk of these symptoms may increase if tacrolimus is taken together with sirolimus or everolimus.

Precautions regarding preparation of the medicine
When preparing the medicine, avoid direct contact with any part of the body such as skin or eyes, or inhalation of products containing tacrolimus in the form of solution, powder, or granules. If such contact occurs, wash the skin and eyes thoroughly.

Prograf and other medicines
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including those purchased without a prescription, as well as herbal supplements. Do not take Prograf together with cyclosporine. If you need to see a doctor other than your transplant specialist, inform the doctor that you are taking tacrolimus. The doctor may wish to consult with your transplant specialist about whether you should take another medicine that may increase or decrease the blood concentration of tacrolimus.

The blood concentration of Prograf may be altered by taking other medicines, and similarly, the blood concentration of other medicines may be altered by taking Prograf. Taking these medicines may require discontinuation of treatment, or an increase or decrease in the dose of Prograf. In some patients, blood levels of tacrolimus have increased when taking other medicines. This may lead to serious adverse effects such as kidney dysfunction, nervous system disorders, and heart rhythm disturbances (see section 4). Changes in the blood concentration of Prograf may occur very quickly after starting another medicine, so frequent and continuous monitoring of Prograf blood levels may be necessary during the first few days after starting another medicine, and often during continued treatment with another medicine.

Some other medicines may cause a decrease in tacrolimus blood levels, which could increase the risk of organ rejection. In particular, inform your doctor if you are currently taking or have recently taken medicines containing the following active substances:

Antifungal and antibiotic medicines, 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), the pharmacokinetic enhancer cobicistat, and combined or non-nucleoside HIV reverse transcriptase inhibitors (efavirenz, etravirine, nevirapine) used to treat HIV infection
HCV protease inhibitors (e.g. telaprevir, boceprevir, ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) used to treat hepatitis C virus infection
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 for peptic ulcer disease and acid reflux (e.g. omeprazole, lansoprazole, or cimetidine)
Antiemetic medicines used to treat nausea and vomiting (e.g. metoclopramide)
Medicines containing aluminium hydroxide and magnesium hydroxide (which neutralize stomach acid), used to treat heartburn
Hormonal medicines containing ethinylestradiol (e.g. oral contraceptives) or danazol
Medicines used for high blood pressure or heart conditions, such as nifedipine, nicardipine, diltiazem, and verapamil
Antiarrhythmic medicines (amiodarone) used to control heart rhythm disturbances (irregular heartbeat)
Medicines known as "statins" used to treat elevated cholesterol and triglyceride levels
Antiepileptic medicines, e.g. carbamazepine, phenytoin, or phenobarbital
Metamizole, used to treat pain and fever
Corticosteroids prednisolone and methylprednisolone
The antidepressant medicine nefazodone
Herbal products containing St. John’s wort (Hypericum perforatum) or Chinese magnolia vine extract (Schisandra sphenanthera)
Cannabidiol (used, among others, to treat epileptic seizures)

Tell your doctor if you are being treated for hepatitis C. Pharmacological treatment of hepatitis C may alter liver function and may affect blood levels of tacrolimus. Tacrolimus blood levels may decrease or increase depending on the medicines prescribed for hepatitis C. Your doctor may wish to closely monitor tacrolimus blood levels and make necessary dose adjustments of Prograf after starting hepatitis C treatment.

Tell your doctor if you are taking or planning to take ibuprofen, amphotericin B, antibiotics (co-trimoxazole, vancomycin, or aminoglycoside antibiotics such as gentamicin), or antiviral medicines (e.g. acyclovir, ganciclovir, cidofovir, or foscarnet). These medicines, when taken together with Prograf, may worsen kidney and nervous system function.

Inform your doctor if you are taking sirolimus or everolimus. If 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).

Tell your doctor if you are taking potassium supplements or potassium-sparing diuretics (e.g. amiloride, triamterene, or spironolactone) or antibiotics trimethoprim or co-trimoxazole, which may increase blood potassium levels, certain pain medicines (so-called NSAIDs - non-steroidal anti-inflammatory drugs, e.g. ibuprofen), anticoagulants, or oral antidiabetic medicines.

If you are due to receive a vaccine, inform your doctor beforehand.

Taking Prograf with food and drink
Avoid eating grapefruit or drinking grapefruit juice during treatment with Prograf.

Pregnancy and breastfeeding
If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, consult your doctor or pharmacist before using this medicine. One study evaluated pregnancy outcomes in women treated with tacrolimus and in women treated with other immunosuppressive medicines. This study did not provide sufficient data to draw definitive conclusions, but a higher rate of miscarriages was observed among liver and kidney transplant patients treated with tacrolimus, as well as a higher rate of persistent proteinuria-related hypertension developing during pregnancy or in the postpartum period (pre-eclampsia) among kidney transplant patients. No increased risk of serious congenital malformations associated with Prograf use has been demonstrated.

Prograf passes into human milk. Therefore, breastfeeding should not be used during treatment with Prograf.

Prograf contains hydrogenated castor oil polyoxyl and ethanol

Prograf contains hydrogenated castor oil polyoxyl, which may cause severe allergic reactions in a small number of patients. Inform your doctor if you have previously experienced such reactions.
Prograf 5 mg/ml concentrate for solution for infusion contains 81% v/v ethanol (alcohol), i.e. 638 mg per dose, 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 use Prograf

Your doctor will determine the initial dose to prevent organ rejection based on your body weight. The usual initial dose administered immediately after transplantation depends on the type of transplanted organ and typically ranges from 0.01 mg/kg body weight/day to 0.10 mg/kg body weight/day.
The concentrate must only be used for intravenous infusion after prior dilution. Prograf will be administered as 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. Afterwards, your doctor will recommend continuing treatment orally by prescribing Prograf capsules.
The dose also depends on your overall health status and on other immunosuppressive medications being used. To determine the appropriate dose and adjust it during treatment, your doctor will recommend regular blood tests.
Use of a higher than recommended dose of Prograf
If a higher dose of Prograf is administered, your doctor will adjust the dose of the next administration.
Discontinuation of Prograf treatment
Stopping Prograf may increase the risk of transplanted organ rejection. Do not discontinue treatment unless instructed by your doctor.
If you have any further questions regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like any medicine, Prograf can cause adverse reactions, although not everyone will experience them.
Prograf suppresses the body's immune defence mechanism to prevent rejection of the transplanted organ.
As a result, the body's ability to fight infections is reduced. Therefore, while taking Prograf, patients are more susceptible than usual to infections such as skin, oral cavity, stomach and gastrointestinal tract, lung, and urinary tract infections. Some infections may be severe or lead to death and may include those caused by bacteria, viruses, fungi, parasites, or other infections.
Inform your doctor immediately if any signs of infection occur, 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 lead to death (progressive multifocal leukoencephalopathy, PML).

Severe adverse reactions may occur, including those listed below.
If any of the following severe adverse reactions have occurred or are suspected, inform your doctor immediately:
Severe adverse reactions occurring frequently (may affect up to 1 in 10 patients):

gastrointestinal perforation: severe abdominal pain, with or without other symptoms such as chills, fever, nausea, or vomiting
dysfunction of the transplanted organ
blurred vision

Severe adverse reactions occurring less frequently (may affect up to 1 in 100 patients):

microangiopathic thrombosis (damage to the smallest blood vessels), including haemolytic uraemic syndrome, a condition with the following symptoms: low urine output or absence of urine (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and unexplained bruising or abnormal bleeding, along with signs of infection

Severe adverse reactions occurring rarely (may affect up to 1 in 1,000 patients):

thrombotic thrombocytopenic purpura: a condition involving damage to the smallest blood vessels, characterised by fever and subcutaneous bruising appearing as red, pinpoint spots, accompanied or not by unexplained extreme fatigue, disorientation, yellowing of the skin or eyes (jaundice), symptoms of acute kidney failure (low urine output or absence of urine), loss of vision, and seizures
toxic epidermal necrolysis: erosion or blistering of the skin or mucous membranes; red, swollen skin may detach over large areas of the body
blindness

Severe adverse reactions occurring very rarely (may affect up to 1 in 10,000 patients):

Stevens-Johnson syndrome: unexplained, widespread skin pain, facial swelling, severe illness with blisters on the skin, mouth, eyes, and genital organs, urticaria, tongue swelling, spreading red or purple skin rash, and peeling of the epidermis
Torsades de pointes: change in heart rate, which may or may not be accompanied by symptoms such as chest pain (angina), fainting, dizziness, or nausea, palpitations (sensation of heart beating), and difficulty breathing

Severe adverse reactions – frequency unknown (frequency cannot be estimated from available data):

opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhoea, fever, and sore throat
benign and malignant tumours during treatment, occurring as a result of immunosuppression, including skin malignancies and a rare type of cancer that may present with skin lesions, known as Kaposi's sarcoma. Symptoms include skin changes such as new or altered pigmentation, spots, or nodules.
pure red cell aplasia (severe reduction in red blood cells), haemolytic anaemia (reduction in red blood cells due to abnormal breakdown, accompanied by fatigue), and neutropenic fever (reduction in white blood cells that fight infection, accompanied by fever). The exact frequency of these adverse reactions is not known. There may be no symptoms, or depending on the severity of the disease, symptoms such as fatigue, apathy, unnatural paleness of the skin (pallor), shortness of breath, dizziness, headache, chest pain, and cold hands and feet may occur.
agranulocytosis (significant reduction in white blood cells accompanied by mouth ulcers, fever, and infection/infections). There may be no symptoms, or sudden increase in body temperature, chills, and sore throat may be experienced.
allergic and anaphylactic reactions with the following symptoms: sudden itchy rash (urticaria), swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and feeling faint
posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood changes, seizures, and blurred vision. These may be symptoms of a disorder known as posterior reversible encephalopathy syndrome, reported in some patients treated with tacrolimus.
optic neuropathy (abnormalities of the optic nerve): vision problems such as blurred vision, changes in colour vision, difficulty perceiving details, or reduced field of vision

The following adverse reactions may also occur after taking Prograf, which may be severe:

Adverse reactions occurring very commonly (may affect more than 1 in 10 people):

increased blood glucose levels, diabetes, increased blood potassium levels
insomnia
muscle tremors, headache
increased blood pressure
abnormal liver function test results
diarrhoea, nausea
kidney dysfunction

Adverse reactions occurring commonly (may affect up to 1 in 10 people):

decreased blood cell count (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell count (visible in blood tests)
decreased blood magnesium, phosphorus, potassium, calcium, or sodium levels, fluid retention, increased blood uric acid or lipid levels, decreased appetite, increased blood acidity, other electrolyte imbalances
anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, psychiatric disorders
seizures, altered consciousness, tingling and numbness (sometimes painful) in hands and feet, dizziness, impaired writing ability, nervous system disorders
increased sensitivity to light, eye disorders
tinnitus
reduced blood flow in heart 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, sore throat, cough, flu-like symptoms
inflammatory conditions or ulceration causing abdominal pain or diarrhoea, gastrointestinal bleeding, inflammation and ulceration of the oral cavity, fluid accumulation in the abdominal cavity, vomiting, abdominal pain, indigestion, constipation, flatulence with gas release, bloating and distension, loose stools, gastrointestinal symptoms
abnormal liver enzyme test results and liver dysfunction, jaundice due to liver disorders, liver cell damage, and hepatitis
itching, rash, hair loss, acne, excessive sweating
joint, limb, back, and foot pain, muscle cramps
kidney failure, reduced urine production, difficulty or painful urination
general weakness, fever, fluid retention, pain and discomfort, increased blood alkaline phosphatase enzyme activity, weight gain, disturbances in body temperature sensation

Adverse reactions occurring less commonly (may affect up to 1 in 100 people):

changes in blood coagulation and bleeding parameters, decreased count of all types of blood cells
dehydration
decreased blood protein or glucose levels, increased blood phosphate levels
coma, intracranial haemorrhage, stroke, paralysis and paresis, brain disorders, speech disorders and dysphasia, memory disorders
lens opacity of the eye
hearing disorders
irregular heartbeat, cardiac arrest, heart failure, myocardial disorders, enlarged heart, stronger heartbeat, abnormal ECG results, abnormal pulse and heart rate
formation of blood clots in limb veins, shock
breathing difficulties, respiratory disorders, asthma
intestinal obstruction, increased blood amylase enzyme activity, regurgitation of stomach contents into the oesophagus, delayed gastric emptying
skin inflammation, photosensitivity
joint disorders
inability to urinate, painful menstruation, and abnormal menstrual bleeding
failure of certain organs, flu-like symptoms, increased sensitivity to heat and cold, chest tightness, nervousness or malaise, increased blood lactate dehydrogenase enzyme activity, weight loss

Adverse reactions occurring rarely (may affect up to 1 in 1,000 people):

small, bloody skin petechiae due to clot formation
increased muscle tone
deafness
fluid accumulation around the heart
acute shortness of breath
pancreatic cyst
impaired blood flow through the liver
hirsutism (excessive hair growth)
thirst, fall, chest tightness, reduced mobility, ulcers

Adverse reactions occurring very rarely (may affect up to 1 in 10,000 people):

muscle weakness
abnormal echocardiogram
liver failure, bile duct stricture
painful urination with blood
increased fatty tissue

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products at Al. Jerozolimskie 181C, PL-02 222 Warsaw, Tel: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder. Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Prograf

Prograf should be stored in a place inaccessible and out of sight of children.
Do not use Prograf after the expiry date stated on the carton and vial following:
{EXP.}. The expiry date refers to the last day of the stated month.
Store in the original packaging to protect from light.
Do not store above 25°C.

6. Contents of the package and other information

What Prograf contains

The active substance is tacrolimus. 1 ml of concentrate for solution for infusion contains 5 mg of tacrolimus.
The other components are: polyoxyl 40 hydrogenated castor oil and dehydrated ethanol.

What Prograf looks like and contents of the pack
The concentrate is a colourless, clear solution supplied in a 1 ml ampoule made of colourless type I glass. Each ampoule contains 1 ml of concentrate for solution for infusion, which must be diluted before administration. Each carton contains 10 ampoules.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation 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 authorised for sale 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

The following information is intended exclusively for medical or healthcare personnel:
Prograf 5 mg/ml concentrate for solution for infusion must not be administered without prior 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 a clear, colourless solution should be administered.
The concentration of the prepared infusion solution should range from 0.004 mg/ml to 0.1 mg/ml.
The total volume of solution for intravenous infusion administered over 24 hours should range from 20 ml to 500 ml.
The diluted solution must not be administered as an intravenous bolus injection.
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.