Label: information for the user

Prograf 5 mg/ml concentrate for infusion solution

Tacrólimus

Read this label carefully before starting to use this medicine, as it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.

• This medicine has been prescribed only for you, and you should not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this label. See section 4.

Contents of the package and additional information

Prografbelongs to a group of medications known as immunosuppressants. After an organ transplant (e.g. liver, kidney, heart), the body's immune system will attempt to reject the new organ.Prograf is used to control the body's immune response, allowing it to accept the transplanted organ.

Prograf is often used in combination with other medications that also suppress the immune system.

You may also receivePrograf to treat an ongoing rejection of your liver, kidney, heart, or other transplanted organ, or if any previous treatment you were following was unable to control this immune response after your transplant.

No use Prograf

• If you are allergic (hypersensitive) to tacrolimus or to any antibiotic belonging to the macrolide subgroup (e.g. erythromycin, clarithromycin, josamycin).
• If you are allergic (hypersensitive) to any of the other components of Prograf (including those listed in section 6), especially to hydrogenated and polyoxylated ricin oil or similar substances.

Advertencias y precauciones

Consult your doctor, pharmacist or nurse before starting to use Prograf.

• While receiving Prograf, your doctor may wish to perform occasional tests (including blood, urine, cardiac function tests, visual and neurological examinations). This is completely normal and will help your doctor decide on the most suitable dose of Prograf for you.
• Please avoid taking any herbal preparations, for example St. John's Wort (Hypericum perforatum) or any other herbal product, as this may affect the effectiveness and dose of Prograf you need to receive. If you have any doubts, please consult your doctor before taking any herbal product.
• If you have liver problems or have had any disease that may have affected your liver, please inform your doctor as this may affect the dose of Prograf you receive.
• If you experience severe abdominal pain accompanied or not by other symptoms such as chills, fever, nausea or vomiting.
• If you have diarrhea for more than one day, please inform your doctor as it may be necessary to adjust the dose of Prograf you receive.
• If you have a heart rhythm disorder called "prolongation of the QT interval".
• Limit your exposure to sunlight and UV light while taking Prograf using suitable protective clothing and using high-factor sunscreen. This is due to the potential risk of malignant skin changes with immunosuppressive therapy.
• If you need to be vaccinated, please inform your doctor beforehand. He will advise you on the best course of action.
• It has been reported that some patients treated with Prograf have increased the risk of developing lymphoproliferative disorders (see section 4). Please ask your doctor for more information about these disorders.
• If you have or have had small blood vessel lesions, known as microangiopathy thrombotic/purpura thrombocytopenic thrombotic/syndrome hemolytic urémic. Inform your doctor if you develop fever, skin hematomas (which may appear as red spots), inexplicable fatigue, confusion, yellow discoloration of the skin or eyes, decreased urine output, vision loss, and convulsions (see section 4). When tacrolimus is taken with sirólimus or everólimus, the risk of these symptoms may increase.

Precautions for handling

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

Other medicines and Prograf

Inform your doctor or pharmacist if you are using, have used recently or may need to use any other medicine, including those purchased without a prescription and herbal preparations.

Prograf should not be used with ciclosporin.

Inform your doctor if you need to visit a doctor other than your transplant specialist. Your doctor may need to consult your transplant specialist if you need to take another medicine that may increase or decrease your tacrolimus blood levels.

The blood levels of Prograf may be modified due to other medicines you are taking, and the blood levels of other medicines may be modified by the administration of Prograf, which may require the interruption, increase or decrease of the Prograf dose.

Some patients have experienced increases in tacrolimus blood levels while taking other medicines. This could cause severe adverse effects, such as kidney problems, nervous system problems, and heart rhythm disorders (see section 4).

The effect on Prograf blood levels can occur very soon after starting to use another medicine, so it may be necessary to monitor the Prograf blood level frequently and continuously during the first days of use of another medicine and with frequency while continuing its use.

Some other medicines may cause tacrolimus blood levels to decrease, which may increase the risk of transplant rejection.

Particularly, you should inform your doctor if you are taking or have taken recently medicines with active principles such as:

• antifungals and antibiotics, especially those called macrolide antibiotics used to treat infections, for example ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid, and flucloxacillin.
• letermovir, used to prevent diseases caused by human cytomegalovirus (CMV).
• inhibitors of HIV protease (for example ritonavir, nelfinavir, saquinavir), the potentiator cobicistat, and combined or non-nucleoside reverse transcriptase inhibitors for HIV (efavirenz, etravirine, nevirapine) used to treat HIV infections.
• inhibitors of HCV protease (for example 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).
• micophenolic acid, used to suppress the immune system as a transplant rejection prevention.
• medicines for stomach ulcers and acid reflux (for example omeprazole, lansoprazole, or cimetidine).
• antiemetics, used to treat nausea and vomiting (for example metoclopramide).
• hydroxide of magnesium-aluminum (antacid), used to treat acidity.
• hormonal treatments with ethinylestradiol (for example oral contraceptive pills) or danazol.
• medicines used to treat hypertension or heart problems, such as nifedipine, nicardipine, diltiazem, and verapamil.
• antiarrhythmic medicines (amiodarone) used to control arrhythmia (irregular heartbeat).
• medicines called "statins" used to treat high cholesterol and triglycerides.
• antiepileptic medicines carbamazepine, phenytoin, or phenobarbital.
• metamizole, used to treat pain and fever.
• corticosteroids prednisone and methylprednisolone.
• the antidepressant nefazodone.
• herbal medicines containing St. John's Wort (Hypericum perforatum) or extracts of Schisandra sphenanthera.
• cannabidiol (its use includes, among others, the treatment of epilepsy).

Inform your doctor if you are receiving treatment for hepatitis C. The pharmacological treatment for hepatitis C may change your liver function and may affect 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 the necessary adjustments to the Prograf dose 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 (for example aciclovir, ganciclovir, cidofovir, foscarnet). These medicines may worsen kidney or nervous system problems when taken together with Prograf.

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

Your doctor also needs to know if you are taking potassium supplements or diuretics that conserve potassium (for example amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim and cotrimoxazole that may increase potassium levels in your blood, some analgesics (the so-called NSAIDs, for example ibuprofen), anticoagulants, or oral medications for diabetes treatment, while receiving Prograf.

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

Use of Prograf with food and drinks

It is recommended to avoid grapefruit or grapefruit juice while receiving Prograf.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant, or if you intend to become pregnant, consult your doctor or pharmacist before using this medicine. A study evaluated the pregnancy outcomes in women treated with tacrolimus and other immunosuppressants. Although there was not enough evidence to draw conclusions in this study, higher rates of spontaneous abortion were reported among patients with liver and kidney transplant treated with tacrolimus, as well as higher rates of persistent hypertension associated with protein loss in the urine among patients with kidney transplant that develops during pregnancy or the postpartum period (a condition called preeclampsia). No increased risk of severe congenital malformations was found associated with the use of Prograf.

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

Prograf contains hydrogenated and polyoxylated ricin oil and ethanol

- Prograf contains hydrogenated and polyoxylated ricin oil that may, in a small number of patients, cause a severe allergic reaction. If you have had this problem before, please inform your doctor.

- This medicine contains 81% ethanol (alcohol), which corresponds to 638 mg per milliliter, equivalent to 16 ml of beer, 7 ml of wine. The small amount of alcohol contained in this medicine does not produce any perceptible effect.

The initial dose to prevent rejection of your transplanted organ will be set by your doctor, calculated based on your body weight. The initial intravenous dose shortly after the transplant will generally be within the range of

0.01-0.10 mg per kg of body weight per day

depending on the transplanted organ.

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

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

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

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

If you use more Prograf than you should

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

If you interrupt treatment with Prograf

Stopping your treatment withPrograf may increase the risk of rejection of your transplanted organ. Do not stop treatment unless your doctor tells you to.

If you have any other questions about the use of this product, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Prograf reduces your body's own defense mechanism that allows you to reject your transplanted organ. Consequently, your body will not function as well as usual in fighting off infections.Therefore, if you are taking Prograf, you will be more prone than usual to suffering infections, for example, skin, mouth, stomach and intestinal, lung, and urinary tract infections.

Some infections can be severe or fatal and may include bacterial, viral, fungal, parasitic, or other infections.

Inform your doctor immediately if you have symptoms of an infection, including:

• Fever, cough, sore throat, feeling of weakness or general discomfort
• Loss of memory, problems thinking, difficulty walking or loss of vision – these symptoms may be due to a rare and severe brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML)

Severe side effects may occur, including those listed below.

Inform your doctor immediately if you suspect you are experiencing any of the following severe side effects:

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

• Perforation of the gastrointestinal tract: severe abdominal pain accompanied or not by other symptoms such as chills, fever, nausea, or vomiting.
• Insufficient function of your transplanted organ.
• Blurred vision.

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

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

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

• Purpura thrombocytopenic thrombosis: includes lesions in smaller blood vessels and is characterized by fever and hemorrhages under the skin that may appear as red spots, with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), with symptoms of acute kidney failure (low or no urine output), 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 in large areas of the body.
• Blindness.

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

• Stevens-Johnson syndrome: inexplicable generalized skin pain, facial swelling, severe illness with blistering of the skin, mouth, eyes, and genitals, rashes, facial swelling, skin peeling.
• Torsades de pointes: a change in heart rate that may or may not be accompanied by symptoms such as chest pain (angina), fainting, dizziness, nausea, palpitations (feeling heartbeats), and difficulty breathing.

Severe side effects of unknown frequency (frequency cannot be estimated from available data):

• Oportunist infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.
• Cancers, both benign and malignant, have been reported as a result of immunosuppression, including malignant skin cancers and a rare type of cancer that may include skin lesions known as Kaposi's sarcoma. Symptoms include skin changes such as new colors or changes to existing ones, lesions, or lumps.
• Pure red cell aplasia (a very significant reduction in red blood cell count), hemolytic anemia (a decrease in red blood cell count due to abnormal rupture accompanied by fatigue), and febrile neutropenia (a decrease in the type of white blood cells that fight infections, accompanied by fever). The exact frequency of these side effects is unknown. You may not have symptoms or, depending on the severity of your condition, you may feel: fatigue, apathy, abnormal paleness of the skin (pallor), difficulty breathing, dizziness, headache, chest pain, and a sensation of cold hands and feet.
• Agranulocytosis (a significant decrease in white blood cell count accompanied by mouth sores, fever, and infection(s)). You may not have symptoms or may feel fever, chills, and sudden sore throat.
• Allergic and anaphylactic reactions with the following symptoms: sudden skin rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing) and may feel like you are going to faint.
• Reversible posterior leukoencephalopathy syndrome (RPLS): headache, confusion, mood changes, seizures, and visual disturbances. These may be signs of a condition known as reversible posterior leukoencephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
• Optic neuropathy (alteration of the optic nerve): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.

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

Frequent 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 tests

-Diarrhea, nausea

-Renal problems

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

-Reduction in the number of blood cells (platelets, red blood cells, or white blood cells), increase in white blood cell count, changes in red blood cell count (see blood test results)

-Decrease in magnesium, phosphate, potassium, calcium, or sodium in the blood, fluid overload, increase in uric acid or lipids in the blood, decrease in appetite, increase in blood acidity, other changes in blood electrolytes

-Anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders

-Seizures, altered consciousness, tingling and numbness (sometimes painful) of hands and feet, dizziness, difficulty writing, nervous system disorders

-Increased sensitivity to light, eye disorders

-Heard sounds in your ears

-Decreased blood flow in cardiac vessels, faster heart rate

-Bleeding, partial or complete blockage of blood vessels, decreased blood pressure

-Difficulty breathing, changes in lung tissue, fluid accumulation around the lung, pharyngitis, cold-like symptoms

-Inflammations or ulcers that cause abdominal pain or diarrhea, stomach hemorrhages, mouth or esophageal ulcers, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, bloating, loose stools, gastrointestinal problems

-Liver function and enzyme changes, skin yellowing due to liver problems, liver tissue damage, and inflammation

-Itching, rash, hair loss, acne, increased sweating

-Pain in joints, extremities, back, and feet, muscle spasms

-Renal insufficiency, decreased urine production, difficulty or pain while urinating

-General weakness, fever, fluid retention, pain and discomfort, increased alkaline phosphatase enzyme in the blood, weight gain, altered sensation of temperature

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

-Changes in blood clotting, decrease in the number of all blood cells

-Dehydration

-Decrease in blood proteins or sugar, increase in phosphate in the blood

-Coma, cerebral hemorrhage, stroke, paralysis, cerebral disorder, speech and language disorders, memory problems

-Corneal opacity

-Difficulty hearing

-Irregular heart rate, heart stoppage, decreased heart function, altered heart muscle, increased heart muscle, stronger heart rate, abnormal electrocardiogram, abnormal heart rate and pulse

-Clots in a vein of an extremity, shock

-Difficulty breathing, respiratory tract disorders, asthma

-Intestinal obstruction, increased blood levels of the amylase enzyme, gastroesophageal reflux, delayed gastric emptying

-Dermatitis, sunburn sensation

-Joint disorders

-Difficulty urinating, painful menstruation, and abnormal menstrual bleeding

-Failure of some organs, illness similar to the flu, increased sensitivity to heat and cold, sensation of pressure in the chest, nervousness or strange sensation, increased lactate dehydrogenase enzyme in the blood, weight loss

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

-Small hemorrhages in your skin due to blood clots

-Increased muscle stiffness

-Deafness

-Fluid accumulation around the heart

-Acute respiratory difficulty

-Pancreatic cysts

-Problems with blood flow in the liver

-Increased body hair

-Thirst, dizziness, sensation of chest pressure, decreased mobility, ulcer

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

-Muscle weakness

-Abnormal echocardiogram

-Liver insufficiency, bile duct narrowing

-Painful urination with blood in the urine

-Increased body fat

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keepout of sight and reach of children.

Do not usethis medicationafter the expiration date that appears on the packaging and on the vial after CAD. The expiration date is the last day of the month indicated.

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

Do not store at a temperature above 25°C.

Composition of Prograf

• The active ingredient is tacrolimus. 1 ml of concentrate for solution for infusion contains 5mg.
• The other components are hydrogenated and polyoxethylene glycolated ricin oil and anhydrous ethanol.

Appearance of the product and contents of the container

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

Eachbox contains 10 vials.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization:

Astellas Pharma, S.A.

Paseo de la Castellana, 259 D - 31st Floor

28046 Madrid (Spain)

Responsible for manufacturing:

Astellas Ireland Co. Limited

Killorglin, County Kerry, V93FC86

Ireland

This medicine is authorized in the member states of the European Economic Area with the following names:

Prograf:

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

Prograft:

Belgium, Luxembourg, Netherlands.

Date of the last review of this leaflet: February 2025

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

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This information is intended solely for doctors or healthcare professionals:

• Prograf 5 mg/ml concentrate for solution for infusion must not be injected without dilution.
• Prograf 5 mg/ml concentrate for solution for infusion must be diluted in a 5% dextrose solution v/v or in physiological saline solution, in polyethylene, polypropylene containers or glass bottles but not in PVC containers. Only transparent and colorless solutions must be used.
• The concentration of the infusion solution must be between 0.004 and 0.100 mg/ml. The total volume of infusion over a period of 24 hours must be 20-500 ml.
• The diluted solution must not be administered as a bolus.
• The infusion solution must be used within a period of 24 hours.

The concentrate for infusion not used in an opened vial or the reconstituted solution not used must be discarded immediately to prevent contamination.