Patient Information Leaflet

Prograf, 0.5 mg, hard capsules
Prograf, 1 mg, hard capsules
Prograf, 5 mg, hard capsules
Tacrolimus
Please read this leaflet carefully before using this medicine, as 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 or pharmacist.
This medicine has been prescribed for you personally. Do not pass it on to others. It may harm someone else, even if their symptoms are the same as yours.
If you experience any side effects, including any not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Leaflet Contents:

What Prograf is and what it is used for
Important information before taking Prograf
How to take 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 help prevent rejection of 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 adequately 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 any of the other ingredients of Prograf (listed in section 6).
If the patient is allergic (hypersensitive) to any macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin).

Warnings and precautions

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

Prograf must be taken every day for as long as immunosuppression is required to prevent rejection of the transplanted organ. The patient should remain under continuous medical supervision.
When taking Prograf, the doctor may order periodic tests (blood tests, urine tests, heart function tests, eye examination, and neurological examination). These are routine tests that help determine the appropriate dose of Prograf.
Herbal products containing St. John’s wort (Hypericum perforatum) and other herbal preparations should be avoided, 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 diarrhea persists for more than one day, inform your doctor, as it may be necessary to adjust the dose of Prograf.
If there is a change in the electrical activity of the heart known as "QT prolongation".
Limit exposure to sunlight and ultraviolet radiation by wearing protective clothing and using high-protection sunscreen. This is due to the risk of developing skin malignancies during immunosuppressive therapy.
If the patient is to receive a vaccine, inform the doctor beforehand. The 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.
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 any of the following occur: fever, bruising under the skin (which may appear as red spots), unexplained fatigue, confusion, jaundice (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: During preparation, avoid direct contact with any part of the body, such as skin or eyes, or inhalation of products containing tacrolimus in solution, powder, or granule form. If such contact occurs, wash the skin and eyes thoroughly.

Prograf and other medicines

Tell your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines planned for use, including over-the-counter medicines and herbal supplements. Prograf must not be taken simultaneously with cyclosporine.

If visiting a doctor other than a transplant specialist, inform the doctor that you are taking tacrolimus. The doctor may wish to consult with the 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 change when other medicines are taken, and the blood concentration of other medicines may also change due to Prograf. The use of these medicines may require interruption of treatment or adjustment (increase or decrease) of the Prograf dose. 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 Prograf blood concentration may occur very quickly after starting another medicine; therefore, frequent and continuous monitoring of Prograf blood levels may be necessary during the first few days after starting another medicine and frequently during continued treatment with another medicine.

Some other medicines may reduce the blood concentration of tacrolimus, which could increase the risk of transplant rejection. In particular, inform your doctor about any medicines currently or recently taken that contain 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 in the treatment of HIV infection
HCV protease inhibitors (e.g. telaprevir, boceprevir, ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elbasvir/grazoprevir, and glecaprevir/pibrentasvir) used in the treatment of hepatitis C virus infection
Nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane (used in the treatment of 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, in the treatment of epileptic seizures)

Tell your doctor if you are being treated for hepatitis C virus infection. Pharmacological treatment of hepatitis C may alter liver function and may affect blood levels of tacrolimus. Tacrolimus blood levels may either 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 treatment for hepatitis C.

Tell your doctor if you are taking or plan 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 Prograf together with potassium supplements, 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 to receive a vaccination, inform your doctor beforehand.

Taking Prograf with food and drink

Prograf should be taken on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal. Avoid consuming grapefruit or grapefruit juice during treatment with Prograf.

Pregnancy and breastfeeding

If the patient is pregnant, breastfeeding, suspects she may be pregnant, or plans to become pregnant, she should consult her doctor or pharmacist before using this medicine. One study evaluated pregnancy outcomes in women treated with tacrolimus and those treated with other immunosuppressive medicines. This study did not provide sufficient data to draw conclusions; however, a higher rate of miscarriage was observed in liver and kidney transplant recipients treated with tacrolimus, and in kidney transplant recipients, a higher incidence of persistent hypertension with proteinuria developing during pregnancy or the postpartum period (pre-eclampsia). No increased risk of serious congenital malformations associated with Prograf use has been demonstrated.

Prograf passes into human milk. Therefore, breastfeeding must not be undertaken during treatment with Prograf.

Driving and operating machinery

Do not drive or operate machinery or tools if dizziness, drowsiness, or visual disturbances occur after taking Prograf. These symptoms occur more frequently if alcohol is consumed during treatment with Prograf.

Prograf contains lactose, sodium, and soya lecithin

Prograf contains lactose. If the patient has previously been diagnosed with intolerance to certain sugars, the patient should consult their doctor before taking this medicine.

This medicine contains less than 1 mmol of sodium (23 mg) per capsule; therefore, this medicine is considered "sodium-free".

The ink used for printing on 0.5 mg and 1 mg Prograf capsules contains soya lecithin. If you are allergic to peanuts or soya, inform your doctor, who will decide whether you should take this medicine.

3. How to use Prograf

Prograf must always be taken exactly as prescribed by your doctor. If in doubt, consult your doctor or pharmacist.
When collecting your prescription, make sure you receive the same medicine containing tacrolimus each time, unless your transplant specialist has specifically advised switching to another tacrolimus-containing medicine. The medicine should be taken twice daily. If the medicine looks different than usual or if dosing instructions have changed, consult your doctor or pharmacist as soon as possible to ensure you have received the correct medicine.

Your doctor will determine the initial dose of Prograf to prevent organ rejection based on your body weight. Usually, the initial dose given immediately after transplantation depends on the type of transplanted organ and typically ranges from 0.075 mg/kg body weight/day to 0.30 mg/kg body weight/day.

The dose also depends on your overall health and other immunosuppressive medicines you are taking. To determine the appropriate dose and adjust it during treatment, your doctor will recommend regular blood tests. Once your clinical condition stabilizes, your doctor may reduce the dose of Prograf. Your doctor will clearly indicate how many capsules to take and how often. Prograf is taken orally twice daily, usually in the morning and evening. Prograf should be taken on an empty stomach, at least 1 hour before or 2 to 3 hours after a meal. Swallow the capsules whole with a glass of water. Avoid consuming grapefruit or grapefruit juice during treatment with Prograf. Do not swallow the desiccant (moisture-absorbing) packet found inside the foil packaging.

Taking more Prograf than prescribed
If you accidentally take more Prograf than prescribed, contact your doctor immediately or go to the nearest hospital.

Missing a dose of Prograf
Do not take a double dose to make up for a missed dose.
If you forget to take your Prograf capsules, wait until the next scheduled dose and then continue taking the medicine according to your regular schedule.

Stopping Prograf treatment
Stopping Prograf may increase the risk of rejecting the transplanted organ. Do not discontinue treatment unless instructed by your doctor.

If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, 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.

Immediately inform your doctor 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).

Serious adverse reactions may occur, including those listed below. If any of the following serious adverse reactions have occurred or are suspected, inform your doctor immediately:

Serious adverse reactions occurring frequently (may occur in less than 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

Serious adverse reactions occurring not frequently (may occur in less than 1 in 100 patients):

thrombotic microangiopathy (damage to the smallest blood vessels), including haemolytic uraemic syndrome, presenting 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

Serious adverse reactions occurring rarely (may occur in less than 1 in 1000 patients):

thrombotic thrombocytopenic purpura: a condition involving damage to the smallest blood vessels, characterised by fever and subcutaneous bruises appearing as red, pinpoint spots, with or without 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 peel off over large areas of the body
blindness

Serious adverse reactions occurring very rarely (may occur in less than 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, nausea, palpitations (sensation of heart beating), and breathing difficulties

Serious 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 due to immunosuppression, including skin malignancies and a rare type of cancer that may present as skin lesions, known as Kaposi's sarcoma. Symptoms include skin changes such as new or changing 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 fighting infections, with concurrent fever). It is not precisely known how often these adverse reactions occur. You may have no symptoms, or depending on the severity of the disease, you may experience fatigue, apathy, unnatural paleness of the skin (pallor), shortness of breath, dizziness, headache, chest pain, and coldness in hands and feet.
agranulocytosis (significant reduction in white blood cells, accompanied by oral ulceration, fever, and infection/infections). You may have no symptoms or may experience sudden increase in body temperature, chills, and sore throat.
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 restricted field of vision

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

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

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

Adverse reactions occurring commonly (may occur in less than 1 in 10 people):

decreased blood cell counts (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell count (visible in blood tests)
decreased levels of magnesium, phosphorus, potassium, calcium, or sodium in the blood, fluid retention, increased levels of uric acid or blood lipids, decreased appetite, increased blood acidity, other electrolyte imbalances
anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, psychiatric disorders
seizures, impaired 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
haemorrhage, 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, bloating and distension, loose stools, gastrointestinal symptoms
abnormal liver enzyme test results and liver function disorders, yellowing of the skin 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 not commonly (may occur in less than 1 in 100 people):

changes in blood coagulation and bleeding parameters, decreased counts of all types of blood cells
dehydration
decreased levels of proteins or glucose in the blood, increased blood phosphate levels
coma, cerebral haemorrhage, stroke, paralysis and paresis, brain disorders, speech and language disorders, memory disturbances
cataract
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 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 occur in less than 1 in 1000 people):

small, bloody skin petechiae due to clot formation
increased muscle tension
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 occur in less than 1 in 10,000 people):

muscle weakness
abnormal echocardiogram
liver failure, bile duct narrowing
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 also be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, 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 to 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.
Hard capsules should be taken immediately after removal from the blister.
Do not use Prograf after the expiry date stated on the carton and blister after:
{EXP.}. The expiry date refers to the last day of the stated month.
Use all capsules within 1 year after opening the aluminium pouch.
There are no special storage temperature requirements for this medicinal product.
Store in the original packaging to protect from moisture.

6. Contents of the pack 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 in the form of tacrolimus monohydrate.
Other components are: capsule contents: hypromellose 6 mPas, sodium croscarmellose, lactose monohydrate, magnesium stearate. capsule shell: titanium dioxide (E171), yellow iron oxide (E172), gelatin. printing ink on the capsule shell: shellac, soybean lecithin, hydroxypropylcellulose, simethicone, red iron oxide (E172).

Prograf 1 mg, hard capsules

The active substance is tacrolimus. Each capsule contains 1 mg of tacrolimus in the form of tacrolimus monohydrate.
Other components are: capsule contents: hypromellose 6 mPas, sodium croscarmellose, lactose monohydrate, magnesium stearate. capsule shell: titanium dioxide (E171), gelatin. printing ink on the capsule shell: shellac, soybean lecithin, hydroxypropylcellulose, simethicone, red iron oxide (E172).

Prograf 5 mg, hard capsules

The active substance is tacrolimus. Each capsule contains 5 mg of tacrolimus in the form of tacrolimus monohydrate.
Other components are: capsule contents: hypromellose 6 mPas, sodium croscarmellose, lactose monohydrate, magnesium stearate. capsule shell: titanium dioxide (E171), red iron oxide (E172), gelatin. printing ink on the capsule shell: shellac, titanium dioxide (E171) and propylene glycol.

What Prograf looks like and contents of the pack
Prograf 0.5 mg, hard capsules
Opaque, light yellow capsules printed with “0.5 mg” and “[f] 607” in red ink, containing white powder.

Prograf 0.5 mg, hard capsules are available in blisters or perforated unit-dose blister packs containing 10 capsules, in a foil package with a desiccant. Do not swallow the desiccant.

Pack sizes containing 20, 30, 50, 60 or 100 hard capsules in blisters and packs of 20x1, 30x1, 50x1, 60x1 or 100x1 hard capsules in perforated unit-dose blister packs are available.

Prograf 1 mg, hard capsules
Opaque, white capsules printed with “1 mg” and “[f] 617” in red ink, containing white powder.

Prograf 1 mg, hard capsules are available in blisters or perforated unit-dose blister packs containing 10 capsules, in a foil package with a desiccant. Do not swallow the desiccant.

Pack sizes containing 20, 30, 50, 60, 90 or 100 hard capsules in blisters and packs of 20x1, 30x1, 50x1, 60x1, 90x1 or 100x1 hard capsules in perforated unit-dose blister packs are available.

Prograf 5 mg, hard capsules
Opaque, reddish-grey capsules printed with “5 mg” and “[f] 657” in white ink, containing white powder.

Prograf 5 mg, hard capsules are available in blisters or perforated unit-dose blister packs containing 10 capsules, in a foil package with a desiccant. Do not swallow the desiccant.

Pack sizes containing 30, 50, 60 or 100 hard capsules in blisters and packs of 30x1, 50x1, 60x1 or 100x1 hard capsules in perforated unit-dose blister packs are available.

Not all pack sizes may be marketed.
On the Polish market, packs of 30 capsules are available.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Astellas Pharma Sp. z o.o.
ul. 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 marketing in 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