Patient Information Leaflet: Information for the User

Prograf 5 mg/ml concentrate for solution for infusion

Tacrolimus
Please read this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this 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 (for example, liver, kidney, or heart), the body's immune system will attempt to reject the new organ. Prograf is used to control the body's immune response, enabling it to accept the transplanted organ.
Prograf is often used in combination with other medicines that also suppress the immune system.
You may also be given Prograf to treat ongoing rejection of a transplanted liver, kidney, heart, or other organ, or if one of the treatments you were taking has proven ineffective in controlling the immune response after transplantation.

2. What you should know before using Prograf

Do not use Prograf

If you are allergic (hypersensitive) to tacrolimus or to any antibiotic belonging to the macrolide subclass of antibiotics (e.g., erythromycin, clarithromycin, josamycin).
If you are allergic (hypersensitive) to any of the excipients (listed in section 6), particularly to polyoxyl 35 hydrogenated castor oil or to similar substances.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Prograf:

While receiving Prograf, your doctor may ask you to undergo periodic tests (including blood and urine tests, heart function monitoring, vision checks, and neurological assessments). This is standard practice and helps your doctor determine the most appropriate dose of Prograf for you.
Please avoid taking any herbal remedies, such as St. John’s wort (Hypericum perforatum), or any other herbal products, as they may alter the effectiveness and required dose of Prograf. If you have any doubts, please consult your doctor before taking any herbal product or remedy.
If you have liver problems or have had a disease that may have damaged your liver, please inform your doctor, as this may affect the dose of Prograf you need to take.
If you experience severe abdominal pain, with or without other symptoms such as chills, fever, nausea, or vomiting.
If you have diarrhea lasting more than one day, inform your doctor, as it may be necessary to adjust your Prograf dose.
If you have an abnormality in the heart's electrical activity known as "QT interval prolongation."
Limit your exposure to sunlight and UV radiation while taking Prograf by wearing protective clothing and using a high-protection sunscreen. This is due to the potential risk of malignant skin changes associated with immunosuppressive therapy.
If you need to receive any vaccination, inform your doctor first. Your doctor will advise you on the best course of action.
It has been reported that patients treated with Prograf have an increased risk of developing lymphoproliferative disorders (see section 4). Ask your doctor for specific information about these disorders.
If you have or have had damage to the 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 small red spots), unexplained fatigue, confusion, yellowing of the skin or eyes, reduced urine output, vision loss, or seizures (see section 4). The risk of developing these symptoms may increase when tacrolimus is taken together with sirolimus or everolimus.

Precautions for handling:
During preparation, avoid direct contact with any part of the body such as the skin or eyes, or inhalation of injectable solutions, powder, or granules contained in tacrolimus-based products. In case of contact, wash the skin and eyes thoroughly.

Other medicines and Prograf
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription and herbal products.
Prograf must not be used together with cyclosporine.
If you visit a doctor other than your transplant specialist, inform them that you are taking tacrolimus. Your doctor may need to consult with your transplant specialist if you require another medicine that could increase or decrease tacrolimus blood levels.
The blood levels of Prograf may be affected by other medicines you are taking, and the blood levels of other medicines may also be altered by Prograf, which may require interruption, increase, or decrease in the dose of Prograf. Some patients have experienced increased blood levels of tacrolimus while taking other medicines. This may cause serious side effects such as kidney problems, nervous system disorders, and heart rhythm disturbances (see section 4).
An effect on Prograf blood levels may occur soon after starting another medicine; therefore, frequent and ongoing monitoring of Prograf blood levels may be necessary in the first days after starting the other medicine and throughout its treatment. Some other medicines may cause a decrease in tacrolimus blood levels, which may increase the risk of transplanted organ rejection. In particular, inform your doctor if you are taking or have recently taken medicines containing active substances such as:

antifungal and antibiotic medicines, particularly so-called 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 a disease caused by CMV (human cytomegalovirus)
HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat, and combination tablets or non-nucleoside reverse transcriptase inhibitors of HIV (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 and prevent transplant rejection
medicines for gastric ulcer or acid reflux (e.g., omeprazole, lansoprazole, or cimetidine)
antiemetic medicines used to treat nausea and vomiting (e.g., metoclopramide)
magnesium-aluminium hydroxide (antacid), used to treat heartburn
hormonal treatments with ethinylestradiol (such as the contraceptive pill) or danazone
medicines for high blood pressure or heart problems such as nifedipine, nicardipine, diltiazem, and verapamil
antiarrhythmic medicines (amiodarone) used to control arrhythmias (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 prednisolone or methylprednisolone
the antidepressant nefazodone
herbal preparations containing St. John’s wort (Hypericum perforatum) or extracts of Schisandra sphenanthera
cannabidiol (uses include, among others, treatment of seizures).

Inform your doctor if you are receiving treatment for hepatitis C. Pharmacological treatment for hepatitis C may alter liver function and 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 after starting hepatitis C treatment.
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, or foscarnet). Using these drugs together with Prograf may worsen any existing kidney or nervous system problems.
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 potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim or cotrimoxazole, which may increase potassium levels in the blood, certain painkillers (so-called non-steroidal anti-inflammatory drugs (NSAIDs), e.g., ibuprofen), anticoagulants, or oral medicines used to treat diabetes, while undergoing treatment with Prograf.
If you need to receive vaccinations, please inform your doctor first.

Prograf with food and drinks
Grapefruit and grapefruit juice must be avoided during treatment with Prograf.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine. In one study, pregnancy outcomes were evaluated in women treated with tacrolimus and in women treated with other immunosuppressants. Although the evidence gathered in this study is not sufficient to draw definitive conclusions, higher rates of spontaneous abortion were reported among liver and kidney transplant recipients treated with tacrolimus, as well as higher rates of persistent hypertension associated with protein loss in the urine developing during pregnancy or the postpartum period (a condition called pre-eclampsia) among kidney transplant recipients. No increased risk of major birth defects has been observed with the use of Prograf.
Prograf is excreted in breast milk. Breastfeeding is therefore not recommended during treatment with Prograf.

Prograf contains polyoxyl 35 hydrogenated castor oil and ethanol

Prograf contains polyoxyl 35 hydrogenated castor oil, which may cause severe allergic reactions in a small number of patients. If you have previously experienced such a reaction, please inform your doctor.
Prograf contains 81% v/v ethanol (alcohol), i.e., up to 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 produce significant effects.

3. How to use Prograf

Your doctor will determine the initial dose to prevent rejection of the transplanted organ, based on your body weight. The initial intravenous dose immediately after transplantation will generally be within the following range:
0.01 - 0.10 mg per kg of body weight per day,
depending on the transplanted organ.
Prograf must only be administered by continuous infusion after dilution. The preparation must be carried out by healthcare professionals. Further instructions for healthcare professionals are provided at the end of this leaflet. You will always receive Prograf as a continuous infusion lasting 24 hours and never as a rapid injection.
Prograf may cause mild irritation if not infused directly into a vein.
Treatment with Prograf should not continue for more than 7 days. Your doctor will then switch you to Prograf capsules.
Your dose depends on your general condition and on any other immunosuppressive medicines you are taking. You will have regular blood tests to determine the correct dose and to adjust it as needed.
If you receive more Prograf than you should
If you have received too much Prograf, your doctor will adjust the subsequent dosage accordingly.
If you stop treatment with Prograf
Stopping treatment with Prograf may increase the risk of rejection of your transplanted organ. Do not discontinue treatment unless your doctor tells you to do so.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, Prograf can cause side effects, although not everybody gets them.
Prograf reduces the body's natural defences to prevent it from rejecting the transplanted organ. As a result, the body may be less able than usual to fight infections. Therefore, if you are taking Prograf, you may get more infections than usual, such as those affecting the skin, mouth, stomach and intestines, lungs, and urinary tract.
Some of these infections may be serious or fatal and may include infections caused by bacteria, viruses, fungi, parasites, or other pathogens.
Inform your doctor immediately if you experience signs of an infection, including:

Fever, cough, sore throat, feeling weak or generally unwell
Memory loss, difficulty thinking, difficulty walking, or loss of vision – these may be due to a rare but serious brain infection that can be fatal (Progressive Multifocal Leukoencephalopathy or PML).

Serious side effects may occur, including those listed below.
Contact your doctor immediately if you have or think you may have any of the following serious side effects:
Serious common side 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.
Poor function of the transplanted organ.
Blurred vision.

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

Thrombotic microangiopathy (damage to the smallest blood vessels), including haemolytic uraemic syndrome, a condition with the following symptoms: reduced or no urine output (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and appearance of bruises (ecchymoses) or abnormal bleeding, and signs of infection.

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

Thrombotic thrombocytopenic purpura, a condition involving damage to the smallest blood vessels, characterised by fever and subcutaneous bruising 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 (reduced or absent 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 large areas of the body.
Blindness.

Serious very rare side 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, swelling of the tongue, red or purplish skin rash that spreads, and skin peeling.
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 (strong awareness of heartbeat), and difficulty breathing.

Serious side effects – frequency not known (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 following treatment due to 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 or changing discoloration, lesions, or nodules.
Cases of pure red cell aplasia (a severe reduction in red blood cell count), haemolytic anaemia (reduced red blood cells due to abnormal destruction, accompanied by fatigue), and febrile neutropenia (a decrease in white blood cells that fight infections, accompanied by fever) have been reported. The exact frequency of these side effects is not known. You may have no symptoms, or depending on the severity, you may experience: fatigue, apathy, unusual paleness of the skin, shortness of breath, dizziness, headache, chest pain, and cold hands and feet.
Cases of agranulocytosis (severely reduced white blood cells, accompanied by mouth ulcers, fever, and infections) have been reported. You may have no symptoms or may experience sudden fever, fever-related chills, and sore throat.
Allergic and anaphylactic reactions with the following symptoms: sudden skin rash with itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and feeling weak.
Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood swings, seizures, and visual disturbances. These may be signs of a condition called posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
Optic neuropathy (abnormality of the optic nerve): vision problems such as blurred vision, changes in colour vision, difficulty seeing details, or restricted visual field.

The following side effects may also occur after taking Prograf and could be serious:
Very common side effects (may affect more than 1 in 10 people):
Increased blood sugar, diabetes mellitus, increased potassium in the blood.
Difficulty sleeping.
Tremor, headache.
Increased blood pressure.
Abnormal liver function test results.
Diarrhoea, nausea.
Kidney problems.
Common side effects (may affect up to 1 in 10 people):
Reduced number of blood cells (platelets, red blood cells, or white blood cells), increased number of white blood cells, abnormalities in red blood cell count (detected in blood tests).
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 salt balance.
Anxiety symptoms, confusion and disorientation, depression, mood swings, nightmares, hallucinations, psychiatric disorders.
Seizures, altered consciousness, tingling and numbness in hands and feet (sometimes painful), dizziness, impaired writing ability, nervous system disorders.
Increased sensitivity to light, eye disorders.
Ringing in the ears.
Reduced blood flow in heart vessels, increased heart rate.
Bleeding, complete or partial blockage of blood vessels, low blood pressure.
Shortness of breath, changes in lung tissue, fluid accumulation around the lung, pharyngitis, cough, flu-like symptoms.
Inflammation or ulcers causing abdominal pain or diarrhoea, bleeding in the stomach, mouth inflammation or ulcers, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, excessive intestinal gas, bloating, loose stools, stomach problems.
Changes in liver function and liver enzymes, 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.
Poor kidney function, reduced urine production, reduced or painful urination.
General weakness, fever, fluid retention in the body, pain and discomfort, increased blood alkaline phosphatase enzyme, weight gain, altered perception of temperature.
Uncommon side effects (may affect up to 1 in 100 people):
Changes in blood clotting processes, reduced count of all blood cells.
Dehydration.
Reduced protein or sugar in the blood, increased phosphate in the blood.
Coma, brain haemorrhage, stroke, paralysis, brain disorders, language and speech disturbances, memory problems.
Lens opacity.
Hearing impairment.
Irregular heartbeat, stopped heartbeat, reduced heart output, heart muscle disorders, thickening of the heart muscle, increased heartbeat, abnormal ECG, altered heart rhythm and rate.
Blood clot in a limb vein, shock.
Breathing difficulties, respiratory disorders, asthma.
Intestinal obstruction, increased blood levels of amylase enzyme, stomach contents refluxing into the throat, delayed gastric emptying.
Dermatitis, burning sensation during sun exposure.
Joint pain.
Inability to urinate, painful menstruation, abnormal menstrual bleeding.
Impairment of certain organs, flu-like illness, increased sensitivity to heat and cold, chest tightness, restlessness and discomfort, increased blood lactate dehydrogenase enzyme, weight loss.
Rare side effects (may affect up to 1 in 1,000 people):
Small skin haemorrhages caused by blood clots.
Increased muscle stiffness.
Deafness.
Fluid accumulation around the heart.
Acute respiratory distress syndrome.
Cyst formation in the pancreas.
Circulatory problems in the liver.
Increased hair growth.
Thirst, fainting, chest tightness, reduced mobility, ulcer.
Very rare side 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 side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
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 cardboard box and on the vial after
"Exp". The expiry date refers to the last day of the month.
Store the vial in its original packaging to protect the medicine from light.
Do not store above 25°C.

6. Package contents 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 excipients are: polyoxyl 40 hydrogenated castor oil and anhydrous ethanol.

Description of the appearance of Prograf and contents of the pack
The concentrate is a clear, colourless solution contained in transparent glass vials.
Each vial contains 1 ml of concentrate for infusion solution, which must be diluted before use.
Each pack contains 10 vials.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Astellas Pharma S.p.A.
Viale Don Luigi Sturzo, 43
20154 Milan (MI)
Italy

Manufacturer:
Astellas Ireland Co. Ltd
Killorglin
County Kerry, V93FC86
Ireland

This medicinal product is authorised in the European Economic Area Member States
under the following names:
Prograf:
Austria, Czech Republic, Denmark, Germany, Greece, Spain, Finland, France, Hungary,
Ireland, Italy, Malta, Norway, Poland, Portugal, Slovakia, Slovenia, Sweden.
Prograft:
Belgium, Luxembourg, Netherlands.

The following information is intended exclusively for physicians or healthcare professionals:
Prograf 5 mg/ml concentrate for solution for infusion must be administered only after dilution. When diluting, this medicinal product must not be mixed with other medicinal products.
Prograf 5 mg/ml concentrate for solution for infusion must be diluted with 5% w/v glucose solution or with sodium chloride physiological saline solution in polyethylene, polypropylene or glass bottles, but not in PVC containers. Only clear and colourless solutions should be used.
The concentration of the infusion solution must be between 0.004 and 0.100 mg/ml. The total volume of infusion over 24 hours must be between 20 and 500 ml.
Do not administer the diluted solution as a bolus.
The infusion solution must be used within 24 hours.
Any unused concentrate for solution for infusion remaining in an opened vial or any unused reconstituted solution must be immediately discarded to avoid contamination.

Package leaflet: Information for the user

Prograf 0.5 mg hard capsules, 1 mg hard capsules, 5 mg hard capsules

Tacrolimus
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again. If you have any questions, consult your doctor or pharmacist. This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful. If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

What Prograf is and what it is used for
What you need to know before taking Prograf
How to take Prograf
Possible side effects
How to store Prograf
Package contents 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 (for example, liver, kidney, or heart), the body's immune system will try to reject the new organ. Prograf is used to control the body's immune response, enabling it to accept the transplanted organ.
Prograf is often used in combination with other medicines that also suppress the immune system.
You may also be given Prograf to treat ongoing rejection of a transplanted liver, kidney, heart, or other organ, or if one of the treatments you were taking has proven unable to control the immune response after transplantation.

2. What you must know before taking Prograf

Do not take Prograf
If you are allergic (hypersensitive) to tacrolimus or to any of the other components of Prograf
(listed in section 6).
If you are allergic (hypersensitive) to any antibiotic belonging to the macrolide subclass of antibiotics
(e.g., erythromycin, clarithromycin, josamycin).

Warnings and precautions
Talk to your doctor or pharmacist before taking Prograf.
You will need to take Prograf every day for as long as immunosuppressive action is required to
prevent rejection of your transplanted organ. Regular contact with your doctor is recommended.
While taking Prograf, your doctor may periodically request a series of tests (including blood and urine
tests, cardiac function monitoring, vision checks, and neurological assessments). This is standard
practice and will help your doctor determine the most appropriate dose of Prograf for you.
Please avoid taking any herbal remedies, for example St. John’s wort (Hypericum perforatum) or any
other herbal product, as they may alter the effectiveness and required dose of Prograf. If in doubt,
please consult your doctor before taking any herbal product or remedy.
If you have liver problems or have had a disease that may have damaged your liver, inform your doctor,
as this may affect the dose of Prograf you need to take.
If you experience severe abdominal pain, with or without other symptoms such as chills, fever, nausea,
or vomiting.
If you have diarrhoea for more than one day, inform your doctor, as your Prograf dose may need to be
adjusted.
If you have a disturbance in the electrical activity of the heart known as “QT interval prolongation”.
Limit your exposure to sunlight and UV radiation while on Prograf therapy by wearing protective
clothing and using a high-protection sunscreen. This is due to the potential risk of malignant skin
changes associated with immunosuppressive therapy.
If you require any vaccination, inform your doctor beforehand. Your doctor will advise you on the best
course of action.
An increased risk of developing lymphoproliferative disorders has been reported in patients treated with
Prograf (see section 4). Ask your doctor for specific information about these disorders.
If you have or have had damage to small blood vessels, known as thrombotic microangiopathy/thrombotic
thrombocytopenic purpura/haemolytic uraemic 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 output, loss of vision, or seizures (see section 4). The risk of developing
these symptoms may increase when tacrolimus is taken together with sirolimus or everolimus.

Handling precautions:
During preparation, avoid direct contact with any part of the body such as skin or eyes, or inhalation of
injectable solutions, powder, or granules contained in tacrolimus-containing products. In case of contact,
wash skin and eyes thoroughly.

Other medicines and Prograf
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines, including over-the-counter medicines and herbal products.
Prograf must not be taken together with ciclosporin.
If you visit a doctor other than your transplant specialist, inform them that you are taking
tacrolimus. The doctor may need to consult with your transplant specialist if you are prescribed a
medicine that could increase or decrease tacrolimus blood levels.
Tacrolimus blood levels may be affected by other medicines you are taking, and the blood levels of
other medicines may be altered by taking Prograf, which may require interruption, increase, or decrease
in the dose of Prograf.
Some patients have experienced increased tacrolimus blood levels while taking other medicines. This
can cause serious side effects such as kidney problems, nervous system disorders, and heart rhythm
disturbances (see section 4).
An effect on Prograf blood levels may occur soon after starting another medicine, so frequent and ongoing
monitoring of Prograf blood levels may be necessary in the first days after starting the other medicine and
throughout its treatment. Some other medicines may cause a decrease in tacrolimus blood levels, which
could increase the risk of transplanted organ rejection. In particular, inform your doctor if you are taking
or have recently taken medicines containing active substances such as:

antifungal and antibiotic medicines, particularly so-called 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 a disease caused by CMV (cytomegalovirus)
HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat, and
combinations in tablets or non-nucleoside reverse transcriptase inhibitors of HIV (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
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 and prevent transplant rejection
medicines for gastric ulcer or acid reflux (e.g., omeprazole, lansoprazole, or cimetidine)
antiemetic medicines used to treat nausea and vomiting (e.g., metoclopramide)
magnesium-aluminium hydroxide (antacid), used to treat heartburn
hormonal treatments with ethinylestradiol (such as contraceptive pills) or danazol
medicines for high blood pressure or heart problems such as nifedipine, nicardipine, diltiazem, and
verapamil
antiarrhythmic medicines (amiodarone) used to control arrhythmias (irregular heartbeat)
medicines known as ‘statins’ used to treat high cholesterol and triglycerides
the antiepileptic medicines carbamazepine, phenytoin, or phenobarbital
metamizole, used to treat pain and fever
the corticosteroids prednisolone or methylprednisolone
the antidepressant nefazodone
herbal preparations containing St. John’s wort (hypericum, Hypericum perforatum) or extracts of
Schisandra sphenanthera
cannabidiol (used, among other things, to treat seizures).

Inform your doctor if you are receiving treatment for hepatitis C. Pharmacological treatment for hepatitis
C can alter liver function and 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 Prograf after starting hepatitis C
treatment.
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, or foscarnet). Using these drugs together with Prograf may worsen kidney or nervous system
problems.
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 haemolytic uraemic 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 or cotrimoxazole, which
can increase potassium levels in the blood, certain painkillers (so-called non-steroidal anti-inflammatory
drugs (NSAIDs), e.g., ibuprofen), anticoagulants, or oral medicines used to treat diabetes, while taking
Prograf.
If you need to receive vaccinations, please inform your doctor beforehand.

Prograf with food and drinks
You should generally take Prograf on an empty stomach, or at least 1 hour before or 2–3 hours after meals.
Grapefruit and grapefruit juice must be avoided during treatment with Prograf.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, ask
your doctor or pharmacist for advice before taking this medicine.
In a study, pregnancy outcomes were evaluated in women treated with tacrolimus and in women treated
with other immunosuppressants. Although the evidence from this study is not sufficient to draw firm
conclusions, higher rates of spontaneous abortion were reported among liver and kidney transplant
recipients treated with tacrolimus, as well as higher rates of persistent hypertension associated with
proteinuria during pregnancy or postpartum (a condition called pre-eclampsia) among kidney transplant
recipients. No increased risk of major birth defects has been observed with the use of Prograf.
Prograf is excreted in breast milk. Therefore, you must not breastfeed during treatment with Prograf.

Driving and using machines
Do not drive and do not operate tools or machinery if you feel unsteady or drowsy, or if you have vision
problems after taking Prograf. These effects are more commonly observed when Prograf is taken with
alcoholic beverages.

Prograf contains lactose, sodium, and lecithin (soy)
Prograf contains lactose. If your doctor has diagnosed you with an intolerance to certain sugars, contact
him or her before taking this medicinal product.
This medicine contains less than 1 mmol of sodium (23 mg) per capsule, i.e., essentially ‘sodium-free’.
The printing ink used on Prograf 0.5 mg and 1 mg capsules contains soy lecithin. If you are allergic to
peanuts or soy, ask your doctor whether you can take this medicine.

3. How to take Prograf

Always take Prograf exactly as prescribed by your doctor. If you have any doubts, consult your doctor or
pharmacist.
Make sure you always receive the same formulation of tacrolimus when collecting your prescription, unless
your transplant specialist has agreed to a change in the tacrolimus formulation.
This medicine must be taken twice daily. If this medicine looks different than usual, or if the dosage
instructions have changed, contact your doctor or pharmacist as soon as possible to ensure you have
received the correct medicine.
The initial dose to prevent rejection of your transplanted organ will be determined by your doctor and
calculated according to your body weight. The initial dose immediately after transplantation will
generally be within the following range:
0.075–0.30 mg per kg of body weight per day,
depending on the transplanted organ.
Your dose depends on your general condition and on which other immunosuppressive medicines you are
taking. You will be required to have regular blood tests so that the correct dose can be determined and
adjusted as needed. Your doctor will usually reduce your dose of Prograf once your condition has
stabilized. Your doctor will tell you exactly how many capsules to take and how often.
Prograf should be taken orally twice daily, usually in the morning and evening. Prograf should generally
be taken on an empty stomach, or at least 1 hour before or 2–3 hours after meals.
The capsules must be swallowed whole with a glass of water. Grapefruit and grapefruit juice must be
avoided during treatment with Prograf. Do not swallow the desiccant contained in the aluminum
wrapper.
If you take more Prograf than you should
If you have accidentally taken too much Prograf, consult your doctor or contact the nearest hospital
emergency department immediately.
If you forget to take Prograf
Do not take a double dose to make up for the missed dose.
If you forget to take your Prograf capsules, wait until the next scheduled dose and then continue as
before.
If you stop taking Prograf
Stopping treatment with Prograf may increase the risk of rejection of your transplanted organ. Do not
discontinue treatment unless your doctor tells you to do so.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, Prograf can cause side effects, although not everyone will experience them.
Prograf reduces the body's natural defence mechanisms to prevent it from rejecting the transplanted organ. As a result, the body will be less effective than usual at fighting infections. Therefore, if you are taking Prograf, you may develop more infections than usual, such as those affecting the skin, mouth, stomach and intestines, lungs, and urinary tract.
Some of these infections may be serious or fatal and may include those caused by bacteria, viruses, fungi, parasites, or other pathogens.
Inform your doctor immediately if you experience signs of an infection, including:
Fever, cough, sore throat, feeling weak or generally unwell
Loss of memory, difficulty thinking, difficulty walking, or loss of vision – these may be due to a very rare and serious brain infection, which can be fatal (Progressive Multifocal Leukoencephalopathy or PML)

Serious side effects may occur, including those listed below. Ask your doctor immediately if you have or think you may have any of the following serious side effects:

Serious common side 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.
Poor function of the transplanted organ.
Blurred vision.

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

Thrombotic microangiopathy (damage to the smallest blood vessels), including haemolytic uraemic syndrome, a condition characterised by the following symptoms: reduced or no urine output (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), appearance of bruises (ecchymoses) or abnormal bleeding, and signs of infection.

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

Thrombotic thrombocytopenic purpura: a condition involving damage to the smallest blood vessels, characterised by fever and subcutaneous bruising appearing as red spots, with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), symptoms of acute kidney failure (reduced or absent 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 large areas of the body.
Blindness.

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

Stevens-Johnson syndrome: unexplained widespread skin pain, facial swelling, a serious illness with blistering of the skin, mouth, eyes, and genitals, hives, swelling of the tongue, red or purplish skin rash that spreads, and skin peeling.
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 (strong awareness of heartbeat), and difficulty breathing.

Serious side effects – frequency not known (frequency cannot be estimated from available data):

Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhoea, fever, sore throat.
Benign and malignant tumours have been reported following treatment, as a consequence of immunosuppression, including malignant skin cancers and a rare type of cancer that may include skin lesions, called Kaposi’s sarcoma. Symptoms include skin changes such as new or changing discoloration, lesions, or nodules.
Cases of pure red cell aplasia (a very severe reduction in red blood cell count), haemolytic anaemia (reduced red blood cell count due to abnormal destruction, accompanied by fatigue), and febrile neutropenia (a decrease in infection-fighting white blood cells, accompanied by fever) have been reported. The exact frequency of these side effects is unknown. You may have no symptoms, or depending on the severity, you may experience: fatigue, apathy, unusual paleness of the skin, shortness of breath, dizziness, headache, chest pain, and cold hands and feet.
Cases of agranulocytosis (severely reduced white blood cell count, accompanied by mouth ulcers, fever, and infections) have been reported. You may have no symptoms or may experience sudden fever, fever-related chills, and sore throat.
Allergic and anaphylactic reactions with the following symptoms: sudden skin rash with itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and feeling weak.
Reversible posterior encephalopathy syndrome (PRES): headache, confusion, mood swings, seizures, and visual disturbances. These may be signs of a disorder called reversible posterior encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
Optic neuropathy (abnormality of the optic nerve): vision problems such as blurred vision, changes in colour vision, difficulty seeing details, or visual field restriction.

Other side effects may also occur after taking Prograf and could be serious:

Very common side effects (may affect more than 1 in 10 people):
Increased blood sugar, diabetes mellitus, increased potassium in the blood.
Difficulty sleeping.
Tremor, headache.
Increased blood pressure.
Abnormal liver function test results.
Diarrhoea, nausea.
Kidney problems.

Common side effects (may affect up to 1 in 10 people):
Reduced number of blood cells (platelets, red blood cells, or white blood cells), increased number of white blood cells, abnormalities in red blood cell count (detected in blood tests).
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 electrolyte balance.
Anxiety symptoms, confusion and disorientation, depression, mood swings, nightmares, hallucinations, mental disorders.
Seizures, altered consciousness, tingling and numbness in hands and feet (sometimes painful), dizziness, impaired writing ability, nervous system disorders.
Increased light sensitivity, eye disorders.
Ringing in the ears.
Reduced blood flow in heart vessels, increased heart rate.
Bleeding, complete or partial blockage of blood vessels, reduced blood pressure.
Shortness of breath, changes in lung tissue, fluid accumulation around the lungs, pharyngitis, 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, excessive intestinal gas, bloating, loose stools, stomach problems.
Changes in liver function and liver enzymes, 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.
Poor kidney function, reduced urine production, reduced or painful urination.
General weakness, fever, fluid retention in the body, pain and discomfort, increased alkaline phosphatase enzyme in the blood, weight gain, altered perception of temperature.

Uncommon side effects (may affect up to 1 in 100 people):
Changes in blood clotting processes, reduced count of all blood cells.
Dehydration.
Reduced protein or blood sugar levels, increased phosphate in the blood.
Coma, brain haemorrhage, stroke, paralysis, brain disorders, language and speech disturbances, memory problems.
Lens opacity.
Hearing impairment.
Irregular heartbeat, stopped heartbeat, reduced heart output, heart muscle disorders, thickening of the heart muscle, increased heart rate, abnormal ECG, altered heart rhythm and rate.
Blood clot in a limb vein, shock.
Breathing difficulties, respiratory disorders, asthma.
Intestinal obstruction, increased blood levels of amylase enzyme, stomach contents refluxing into the throat, delayed gastric emptying.
Dermatitis, burning sensation upon sun exposure.
Joint pain.
Inability to urinate, painful menstruation, abnormal menstrual bleeding.
Impairment of certain organs, flu-like illness, increased sensitivity to heat and cold, chest tightness, restlessness and discomfort, increased blood lactate dehydrogenase enzyme, weight loss.

Rare side effects (may affect up to 1 in 1,000 people):
Small skin haemorrhages caused by blood clots.
Increased muscle stiffness.
Deafness.
Fluid accumulation around the heart.
Acute respiratory distress syndrome.
Cyst formation in the pancreas.
Circulatory problems in the liver.
Increased hair growth.
Thirst, fainting, chest tightness, reduced mobility, ulcer.

Very rare side 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.
Increase in fatty tissue.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor or pharmacist. You may also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
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.
Hard capsules should be taken immediately after removal from the blister.
Do not use Prograf after the expiry date stated on the cardboard box and blister after 'Exp.'. The expiry date refers to the last day of the month. Prograf capsules must be used within 1 year of opening the aluminium wrapper.
This medicine does not require any special storage conditions.
Store in the original packaging to protect the medicine from moisture.

6. Package contents and other information

What Prograf contains
Prograf 0.5 mg hard capsules

The active substance is tacrolimus. Each capsule contains 0.5 mg of tacrolimus as tacrolimus monohydrate.
The other components are: Capsule contents: hypromellose, sodium croscarmellose, lactose monohydrate, magnesium stearate. Capsule shell: titanium dioxide (E 171), yellow iron oxide (E 172), gelatin. Printing ink for the capsule shell: shellac, lecithin (soy), hydroxypropylcellulose, simethicone, red iron oxide (E 172).

Prograf 1 mg hard capsules

The active substance is tacrolimus. Each capsule contains 1 mg of tacrolimus as tacrolimus monohydrate.
The other components are: Capsule contents: hypromellose, sodium croscarmellose, lactose monohydrate, magnesium stearate. Capsule shell: titanium dioxide (E 171), gelatin. Printing ink for the capsule shell: shellac, lecithin (soy), hydroxypropylcellulose, simethicone, red iron oxide (E 172).

Prograf 5 mg hard capsules

The active substance is tacrolimus. Each capsule contains 5 mg of tacrolimus as tacrolimus monohydrate.
The other components are: Capsule contents: hypromellose, sodium croscarmellose, lactose monohydrate, magnesium stearate. Capsule shell: titanium dioxide (E 171), red iron oxide (E 172), gelatin. Printing ink for the capsule shell: shellac, titanium dioxide (E 171), and propylene glycol.

Description of the appearance of Prograf and package contents
Prograf 0.5 mg hard capsules
Light yellow, opaque capsules imprinted in red with "0.5 mg" and "[f] 607", containing white powder. Prograf 0.5 mg hard capsules are packed in blisters or in unit-dose divisible blisters, each containing 10 capsules inside a protective wrapper with a desiccant to protect the capsules from moisture. The desiccant must not be ingested. Pack sizes of 20, 30, 50, 60, and 100 hard capsules are available, as well as unit-dose divisible blister packs of 20×1, 30×1, 50×1, 60×1, and 100×1 hard capsules.

Prograf 1 mg hard capsules
White, opaque capsules imprinted in red with "1 mg" and "[f] 617", containing white powder. Prograf 1 mg hard capsules are packed in blisters or in unit-dose divisible blisters, each containing 10 capsules inside a protective wrapper with a desiccant to protect the capsules from moisture. The desiccant must not be ingested. Pack sizes of 20, 30, 50, 60, 90, and 100 hard capsules are available, as well as unit-dose divisible blister packs of 20×1, 30×1, 50×1, 60×1, 90×1, and 100×1 hard capsules.

Prograf 5 mg hard capsules
Greyish-red, opaque capsules imprinted in white with "5 mg" and "[f] 657", containing white powder. Prograf 5 mg hard capsules are packed in blisters or in unit-dose divisible blisters, each containing 10 capsules inside a protective wrapper with a desiccant to protect the capsules from moisture. The desiccant must not be ingested. Pack sizes of 30, 50, 60, and 100 hard capsules are available, as well as unit-dose divisible blister packs of 30×1, 50×1, 60×1, and 100×1 hard capsules.

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder:
Astellas Pharma S.p.A.
Viale Don Luigi Sturzo, 43
20154 Milan (MI)
Italy

Manufacturer:
Astellas Ireland Co. Ltd
Killorglin
County Kerry, V93FC86
Ireland

This medicinal product is authorized in the European Economic Area countries under the following names:
Prograf:
Austria, Cyprus, Czech Republic, Denmark, Germany, Greece, Spain, Finland, France, Hungary, Ireland, Italy, Malta, Norway, Poland, Portugal, Slovakia, Slovenia, Sweden.
Prograft:
Belgium, Luxembourg, Netherlands.