PROGRAF 5 mg HARD CAPSULES

Introduction

Package Leaflet: Information for the User

Prograf 0.5 mg hard capsules

Prograf 1 mg hard capsules

Prograf 5 mg hard capsules

Tacrolimus

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.

• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information

1. What is Prograf and what is it used for
2. What you need to know before you take Prograf
3. How to take Prograf
4. Possible side effects
5. Storing Prograf
6. Contents of the pack and further information

1. What is Prograf and what is it used for

Prograf belongs to a group of medicines called immunosuppressants. After your organ transplant (e.g. liver, kidney, heart), your body's immune system will try to reject the new organ. Prograf is used to control your body's immune response, allowing it to accept the transplanted organ.

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

You may also receive Prograf to treat rejection that is occurring in your liver, kidney, heart, or other transplanted organ, or if any previous treatment you were following did not control this immune response after your transplant.

2. What you need to know before you take Prograf

Do not take Prograf

• If you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Prograf (listed in section 6).
• If you are allergic (hypersensitive) to any antibiotic belonging to the subgroup of antibiotics called macrolides (e.g. erythromycin, clarithromycin, josamycin).

Warnings and precautions

Consult your doctor or pharmacist before taking Prograf

• You will need to take Prograf every day, as long as you need immunosuppression to prevent rejection of your transplanted organ. You should remain in regular contact with your doctor.
• While taking Prograf, your doctor may want to perform various tests from time to time (including blood and urine tests, heart function tests, visual and neurological tests). This is quite normal and will help your doctor to decide the most suitable dose of Prograf for you.
• Please avoid taking any herbal preparations, e.g. St. John's Wort (Hypericum perforatum) or any other plant-based products, as this may affect the effectiveness and dose of Prograf that you need to receive. If you are in doubt, please consult your doctor before taking any such products or preparations.
• If you have liver problems or have had a disease that may have affected your liver, please inform your doctor, as this may affect the dose of Prograf that you receive.
• If you experience severe abdominal pain accompanied by other symptoms such as chills, fever, nausea, or vomiting.
• If you have diarrhea for more than a day, please inform your doctor, as it may be necessary to adjust the dose of Prograf that you receive.
• If you have an alteration in the electrical activity of the heart called "prolongation of the QT interval".
• Limit your exposure to sunlight and UV light while taking Prograf by using protective clothing and sunscreen with a high sun protection factor. 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 an increased risk of developing lymphoproliferative disorders (see section 4). Ask your doctor for more information about these disorders.
• If you have or have had damage to the small blood vessels, known as microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Inform your doctor if you develop fever, bruising under the skin (which may appear as red spots), unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urine output, loss of vision, and seizures (see section 4). When tacrolimus is taken together with sirolimus or everolimus, the risk of these symptoms may increase.

Handling precautions:

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

Other medicines and Prograf

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription and plant-based preparations.

Prograf should not be taken with ciclosporin.

If you need to visit a different doctor than your transplant specialist, tell the doctor that you are taking tacrolimus. Your doctor may need to consult your transplant specialist if you need to use another medicine that may increase or decrease your blood level of tacrolimus.

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

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

The effect on Prograf blood levels can occur soon after starting to use another medicine, so it may be necessary to monitor the blood level of Prograf frequently and continuously during the first few days of use of another medicine and frequently while continuing its use. Some other medicines may cause the blood levels of tacrolimus to decrease, which may increase the risk of rejection of the transplanted organ. In particular, you should inform your doctor if you are taking or have recently taken medicines with active ingredients such as:

• antifungals and antibiotics, especially those 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 diseases caused by CMV (human cytomegalovirus)

• HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), the pharmacokinetic enhancer cobicistat, and the combination or non-nucleoside reverse transcriptase inhibitors for 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 as a prevention of transplant rejection
• medicines for stomach ulcers and acid reflux (e.g. omeprazol, lansoprazol, or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
• magnesium-aluminum hydroxide (antacid), used to treat acidity
• hormonal treatments with ethinylestradiol (e.g. the oral contraceptive pill) or danazol
• medicines used to treat high blood pressure or heart problems, such as nifedipine, nicardipine, diltiazem, and verapamil
• antiarrhythmic medicines (amiodarone) used to control 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 prednisone and methylprednisolone
• the antidepressant nefazodone
• plant-based medicines containing St. John's Wort (Hypericum perforatum) or extracts of Schisandra sphenanthera
• cannabidiol (its use includes, among others, the treatment of epileptic seizures).

Tell your doctor if you are receiving treatment for hepatitis C. The pharmacological treatment for hepatitis C may change your liver function and may affect the blood levels of tacrolimus. The blood levels of tacrolimus may decrease or increase depending on the medicines prescribed for hepatitis C. Your doctor may need to closely monitor the blood levels of tacrolimus and make the necessary dose adjustments of Prograf after starting treatment for hepatitis C.

Tell 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, foscarnet). These medicines may worsen kidney or nervous system problems when taken together with Prograf.

Tell your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken together with sirolimus or everolimus, the risk of 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 and cotrimoxazole, which may increase the levels of potassium in your blood, some painkillers (the so-called NSAIDs, e.g. ibuprofen), anticoagulants, or oral medication for the treatment of diabetes, while taking Prograf.

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

Taking Prograf with food and drink

Prograf should generally be taken on an empty stomach or at least 1 hour before a meal or 2-3 hours after it. You should avoid grapefruit or grapefruit juice while taking Prograf.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. A study evaluated the outcomes of pregnancy in women treated with tacrolimus and with other immunosuppressants. Although this study did not provide enough evidence to draw conclusions, higher rates of spontaneous abortion were reported among liver and kidney transplant patients treated with tacrolimus, as well as higher rates of persistent hypertension, associated with protein loss in the urine, among kidney transplant patients that develop during pregnancy or the postpartum period (a condition called preeclampsia). No increased risk of serious congenital anomalies was found with the use of Prograf.

Prograf passes into breast milk. Therefore, you should not breast-feed while receiving Prograf.

Driving and using machines

Do not drive or operate tools or machines if you feel dizzy or drowsy, or have problems seeing clearly after taking Prograf. These effects are more common when Prograf is taken with alcohol.

Prograf contains lactose, sodium, and lecithin (soya)

This medicine contains lactose. If your doctor has told you that you have an intolerance to some sugars, consult them before taking this medicine.

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

The printing ink used in Prograf 0.5 mg and 1 mg capsules contains soya lecithin. If you are allergic to peanuts or soya, consult your doctor to determine if you should use this medicine.

3. How to take Prograf

Follow exactly the instructions for taking Prograf as given by your doctor. If you are in doubt, consult your doctor or pharmacist again.

Make sure you receive the same medicine with tacrolimus each time you collect your prescription, unless your transplant specialist has agreed to change to a different tacrolimus medicine. This medicine should be taken twice a day. If the appearance of this medicine is not the same as usual, or if the dosage instructions have changed, consult your doctor or pharmacist as soon as possible to ensure you have the correct medicine.

The initial dose to prevent rejection of your transplanted organ will be determined by your doctor based on your body weight. The initial doses immediately after transplantation will generally be within the range of 0.075-0.30 mg per kg body weight and per day, depending on your transplanted organ.

Your dose depends 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. 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 is taken orally, twice a day, usually in the morning and evening. You should generally take Prograf on an empty stomach or at least 1 hour before, or 2-3 hours after a meal. The capsules should be swallowed whole with a glass of water. Avoid grapefruit or grapefruit juice while taking Prograf. Do not ingest the desiccant included in the aluminum blister.

If you take more Prograf than you should

If you accidentally take more Prograf than you should, consult your doctor or go to the emergency department of the nearest hospital or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medicine and the amount taken.

If you forget to take Prograf

Do not take a double dose to make up for forgotten doses.

If you forget to take Prograf capsules, wait until the next dose and then continue as before.

If you stop taking Prograf

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

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Prograf reduces the body's defense mechanism that allows it to reject the transplanted organ. Consequently, the body will not work as well as usual in fighting infections. Therefore, if you are taking Prograf, you will be more prone than usual to suffer from infections, such as skin, mouth, stomach, and intestinal infections, lung and urinary tract infections.

Some infections can be severe or fatal and may include infections caused by bacteria, viruses, fungi, parasites, or other infections.

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

• Fever, cough, sore throat, feeling of weakness or general malaise
• Memory loss, problems thinking, difficulty walking, or loss of vision - these symptoms may be due to a rare and severe brain infection (progressive multifocal leukoencephalopathy or PML)

Severe adverse effects may occur, including those listed below.

Inform your doctor immediately if you suspect you are suffering from any of the following severe adverse effects:

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

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

Infrequent severe adverse effects (may affect up to 1 in 100 people):

• Thrombotic microangiopathy (lesions in small 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 bruising or abnormal bleeding and signs of infection.

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

• Thrombotic thrombocytopenic purpura: includes lesions in small blood vessels and is characterized by fever and bruising 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, reddened and swollen skin that may peel off in large areas of the body.
• Blindness.

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

• Stevens-Johnson syndrome: unexplained generalized skin pain, facial swelling, severe disease with blistering of the skin, mouth, eyes, and genitals, rash, swelling of the tongue, red or purple skin rash that spreads, peeling of the skin.
• 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 (feeling heartbeats) and difficulty breathing.

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

• Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.
• Benign and malignant tumors have been reported after treatment 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 in existing ones, lesions, or lumps.
• Cases of pure red cell aplasia (a significant reduction in red blood cell count), hemolytic anemia (reduction in red blood cell count due to abnormal breakdown of red blood cells, accompanied by fatigue), and febrile neutropenia (a decrease in the type of white blood cells that fight infections, accompanied by fever) have been reported. The exact frequency of these adverse effects is unknown. You may not have symptoms or, depending on the severity of the condition, you may feel: fatigue, apathy, abnormal paleness of the skin (pallor), difficulty breathing, dizziness, headache, chest pain, and feeling cold in hands and feet.
• Cases of agranulocytosis (a significant decrease in white blood cell count, accompanied by mouth sores, fever, and infection). You may not have symptoms or you may feel sudden fever, chills, and sore throat.
• Allergic reactions and anaphylaxis with the following symptoms: sudden itchy skin rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and you may feel like you are going to faint.
• Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood changes, seizures, and vision changes. These could be signs of a disorder known as posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
• Optic neuropathy (nerve damage): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced field of vision.

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

Very frequent adverse effects (may affect more than 1 in 10 people):

• Increased blood sugar, diabetes mellitus, increased potassium in the blood
• Difficulty sleeping
• Tremors, headache
• Increased blood pressure

Liver function test abnormalities

• Diarrhea, nausea
• Kidney problems

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

• Reduction in blood cell count (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell count (see blood test)
• 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 salts
• Anxiety symptoms, confusion and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders
• Seizures, alterations in consciousness, tingling and numbness (sometimes painful) of hands and feet, dizziness, difficulty writing, nervous system disorders
• Increased sensitivity to light, eye disorders
• Hearing sounds in the ears
• Decreased blood flow in the heart 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, inflammation of the pharynx, common cold, flu-like symptoms
• Inflammations or ulcers that cause abdominal pain or diarrhea, stomach bleeding, mouth ulcers, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, bloating, loose stools, stomach problems
• Changes in liver function and enzymes, jaundice of the skin due to liver problems, liver tissue damage, and liver inflammation
• Itching, rash, hair loss, acne, increased sweating
• Pain in joints, limbs, back, and feet, muscle spasms
• Insufficient kidney function, decreased urine production, difficulty or pain when urinating
• General weakness, fever, fluid retention, pain, and discomfort, increased alkaline phosphatase in the blood, weight gain, altered temperature sensation

Infrequent adverse effects (may affect up to 1 in 100 people):

• Changes in blood coagulation, decrease in all blood cell counts
• Dehydration
• Decreased protein or sugar in the blood, increased phosphate in the blood
• Coma, cerebral hemorrhage, stroke, paralysis, brain disorder, speech and language disorders, memory problems
• Cataract
• Hearing difficulty
• Irregular heartbeat, cardiac arrest, decreased heart function, heart muscle disorder, increased heart muscle, stronger heartbeat, abnormal electrocardiogram, abnormal heart rate and pulse
• Blood clots in a limb vein, shock
• Breathing difficulties, respiratory tract disorders, asthma
• Intestinal obstruction, increased blood amylase level, stomach content reflux in the throat, delayed stomach emptying
• Dermatitis, burning sensation under sunlight
• Joint disorders
• Difficulty urinating, painful and abnormal menstrual bleeding
• Failure of some organs, flu-like illness, increased sensitivity to heat and cold, feeling of pressure in the chest, nervousness or strange feeling, increased lactate dehydrogenase in the blood, weight loss

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

• Small bleeding spots on the skin due to blood clots
• Increased muscle stiffness
• Deafness
• Fluid accumulation around the heart
• Acute breathing difficulties
• Pancreatic cyst formation
• Liver blood flow problems
• Increased hair growth
• Thirst, falls, feeling of chest pressure, decreased mobility, ulcers

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

• Muscle weakness
• Abnormal echocardiogram
• Liver failure, bile duct narrowing
• Painful urination with blood in the urine
• Increased fatty tissue

Reporting Adverse Effects

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

5. Storage of Prograf

Keep Prograf out of sight and reach of children.

Take the hard capsules immediately after removing them from the blister pack.

Do not use this medicine after the expiration date shown on the packaging and on the blister pack after CAD. The expiration date is the last day of the month indicated.

Use all the capsules within 1 year of opening the aluminum bag.

This medicine does not require special storage conditions.

Keep in the original packaging to protect it from moisture.

Medicines should not be disposed of via wastewater or household waste. Deposit the packaging and medicines you no longer need at the pharmacy's SIGRE point. If in doubt, ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Prograf

Prograf 0.5 mg hard capsules

• The active ingredient is tacrolimus. Each capsule contains 0.5 mg of tacrolimus as tacrolimus monohydrate.
• The other ingredients are:

Capsule content: hypromellose, croscarmellose sodium, lactose monohydrate, magnesium stearate.

Capsule shell: titanium dioxide (E 171), yellow iron oxide (E 172), gelatin.

Capsule shell printing ink: shellac, lecithin (from soy), hydroxypropyl cellulose, simethicone, red iron oxide (E172).

Prograf 1 mg hard capsules

• The active ingredient is tacrolimus. Each capsule contains 1 mg of tacrolimus as tacrolimus monohydrate.
• The other ingredients are:

Capsule content: hypromellose, croscarmellose sodium, lactose monohydrate, magnesium stearate.

Capsule shell: titanium dioxide (E 171), gelatin.

Capsule shell printing ink: shellac, lecithin (from soy), hydroxypropyl cellulose, simethicone, red iron oxide (E172).

Prograf 5 mg hard capsules

• The active ingredient is tacrolimus. Each capsule contains 5 mg of tacrolimus as tacrolimus monohydrate.
• The other ingredients are:

Capsule content: hypromellose, croscarmellose sodium, lactose monohydrate, magnesium stearate.

Capsule shell: titanium dioxide (E 171), red iron oxide (E 172), gelatin.

Capsule shell printing ink: shellac, titanium dioxide (E 171), and propylene glycol.

Product Appearance and Package Contents

Prograf 0.5 mg hard capsules

Light yellow opaque capsules printed in red with "0.5 mg" and "[f] 607" containing white powder.

Prograf 0.5 mg hard capsules are available in blister packs or in single-dose blister packs with 10 capsules inside an aluminum protective bag, which includes a desiccant that protects the capsules from moisture. Do not swallow the desiccant.

Available packages are 20, 30, 50, 60, and 100 hard capsules in blister packs, and 20, 30, 50, 60, and 100 hard capsules in single-dose blister packs.

Prograf 1 mg hard capsules

White opaque capsules printed in red with "1 mg" and "[f] 617" containing white powder.

Prograf 1 mg hard capsules are available in blister packs or in single-dose blister packs with 10 capsules inside an aluminum protective bag, which includes a desiccant that protects the capsules from moisture. Do not swallow the desiccant.

Available packages are 20, 30, 50, 60, 90, and 100 hard capsules in blister packs, and 20, 30, 50, 60, 90, and 100 hard capsules in single-dose blister packs.

Prograf 5 mg hard capsules

Grayish-red opaque capsules printed in white with "5 mg" and "[f] 657" containing white powder.

Prograf 5 mg hard capsules are available in blister packs or in single-dose blister packs with 10 capsules inside an aluminum protective bag, which includes a desiccant that protects the capsules from moisture. Do not swallow the desiccant.

Available packages are 30, 50, 60, and 100 hard capsules in blister packs, and 30, 50, 60, and 100 hard capsules in single-dose blister packs.

Not all package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Astellas Pharma, S.A.

Paseo de la Castellana, 259 D - 31st floor

28046 Madrid (Spain)

Manufacturer:

Astellas Ireland Co. Limited

Killorglin

County Kerry, V93FC86

Ireland

This Medicine is Authorized in the Member States of the European Economic Area under the Following Names:

Prograf:

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

Prograft:

Belgium, Luxembourg, Netherlands.

Date of the Last Revision of this Prospectus:February 2025

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