Package Insert: Information for the User

Prograf 0.5 mg Hard Capsules

Prograf 1 mg Hard Capsules

Prograf 5 mg Hard Capsules

Tacrolimus

Read this package insert carefully before you start taking this medicine because it contains important information for you.

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

• This medicine has been prescribed for you only, and you must 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 or pharmacist, even if they are not listed in this package insert. See section 4.

Prografbelongs to a group of medications known as immunosuppressants. After an organ transplant (for example, liver, kidney, heart), your body's immune system will attempt to reject the new organ.Prograf is used to control your body's immune response, allowing you 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 a rejection that is occurring in your liver, kidney, heart, or other transplanted organ, or if anyprevious treatment you were following, fails to control this immune response after your transplant.

No take Prograf

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

Warnings and Precautions

Consult your doctor or pharmacist before starting to take Prograf

• You will need to take Prograf every day, as long as you need immunosuppression to prevent rejection of your transplanted organ. You should stay in regular contact with your doctor.
• While taking Prograf, your doctor may wish to perform occasional tests (including blood and urine tests, cardiac function tests, visual and neurological examinations). This is completely normal and will help your doctor to 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 efficacy and dose of Prograf you need to receive. If you have any doubts, please consult your doctor before taking any herbal product or preparation.
• 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 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 protective clothing and using a 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 injuries, known as microangiopathy, thrombotic purpura, thrombocytopenic purpura, or hemolytic uremic syndrome. Inform your doctor if you develop fever, skin hemorrhages (which may appear as red spots), unexplained fatigue, confusion, yellow discoloration of the skin or eyes, decreased urine output, vision loss, and seizures (see section 4). When tacrolimus is taken with sirolimus or everolimus, 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 taken with cyclosporin.

If you need to visit a doctor other than your transplant specialist, tell the doctor that you are taking tacrolimus.Your doctor may need to consult with your transplant specialist if you need to use another medicine that may increase or decrease your 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 be affected by the administration of Prograf, which may require the interruption, increase, or decrease of the Prograf dose.

Some patients have experienced increased 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 another medicine, so it may be necessary to monitor Prograf blood levels frequently and continuously during the first days of use of another medicine and frequently while continuing its use.Some other medicines may cause tacrolimus blood levels to decrease, which may increase the risk of organ transplant rejection.In particular, you should inform your doctor if you are taking or have taken recently medicines with active principles such as:

• antifungals and antibiotics, especially 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).
• protease inhibitors for HIV (e.g. ritonavir, nelfinavir, saquinavir), the potentiator cobicistat, and combined or non-nucleoside reverse transcriptase inhibitors for HIV (efavirenz, etravirine, nevirapine) used to treat HIV infections.

• protease inhibitors for HCV (e.g. telaprevir, boceprevir, the combination ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, elbasvir/grazoprevir, and glecaprevir/pibrentasvir), used to treat HCV infections.
• 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 prevention of transplant rejection.
• medicines for stomach ulcers and acid reflux (e.g. omeprazole, lansoprazole, or cimetidine).
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide).
• magnesium hydroxide-aluminum (antacid), used to treat acidity.
• hormonal treatments with ethinylestradiol (e.g. the oral contraceptive pill) 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).
• statins used to treat high cholesterol and triglycerides.
• antiepileptic medicines carbamazepine, phenytoin, or phenobarbital.
• metamizole, used to treat pain and fever.
• prednisone and methylprednisolone corticosteroids.
• nefazodone antidepressant.
• herbal medicines containing St. John's Wort (Hypericum perforatum) or Schisandra sphenanthera extracts.
• 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 (e.g. 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 sirolimus or everolimus. When tacrolimus is taken with sirolimus or everolimus, the risk of microangiopathy, thrombotic purpura, and hemolytic uremic syndrome may increase (see section 4).

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

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

Prograf with Food and Drinks

Generally, you should take Prograf on an empty stomach or at least 1 hour before meals or 2-3 hours after them. You should avoid grapefruit or grapefruit juice while taking 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 outcomes of pregnancy in women treated with tacrolimus and other immunosuppressants. Although there was not enough evidence to draw conclusions in this study, there were reported higher rates of spontaneous abortion 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 develops during pregnancy or the postpartum period (a condition called preeclampsia). There was no increased risk of severe congenital malformations associated with Prograf use.

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

Driving and Operating Machines

Do not drive and do not operate tools or machines if you feel dizzy or drowsy, or if you have problems seeing clearly after taking Prograf. These effects are more common if 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 a certain sugar intolerance, consult with him before taking this medicine.

This medicine contains less than 1 mmol of sodium (23 mg) per capsule; it 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.

Follow exactly the administration instructions for Prograf indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Make sure you receive the same tacrolimus-containing medication every time you pick up your prescription, unless your transplant specialist has agreed to switch to a different tacrolimus-containing medication. This medication should be taken twice a day. If the appearance of this medication is not the same as always, or if the dosing instructions have changed, consult your doctor or pharmacist as soon as possible to ensure you have the correct medication.

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

0.075-0.30 mg per kg of body weight and per day

depending on the transplanted organ.

Your dose will depend on your overall 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 Prograf dose 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 at night. In general, you should take Prograf on an empty stomach or at least one hour before, or 2 to 3 hours after eating. The capsules should be swallowed whole with a glass of water. Avoid grapefruit and grapefruit juice while taking Prograf. Do not ingest the desiccant included in the aluminum bag.

If you take more Prograf than you should

If you accidentally take morePrografthan you should, consult your doctor or go to the nearest hospital emergency department or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medication and the amount ingested.

If you forget to take Prograf

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

If you forget to takePrograf capsules, wait until the next scheduled dose and then continue as usual.

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 from infections, for example, skin, mouth, stomach and intestinal, 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 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 disease 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 following 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 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 feeling of coldness in your 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), sudden 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, flu-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, swelling, loose stools, gastrointestinal problems

-Liver function and enzyme changes, yellowing of the skin 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 temperature sensation

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

-Cloudy cornea

-Difficulty hearing

-Irregular heartbeat, cardiac arrest, decreased heart function, altered heart muscle, increased heart muscle, stronger heartbeat, 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 amylase enzyme, gastroesophageal reflux, delayed gastric emptying

-Dermatitis, sunburn sensation

-Joint disorders

-Difficulty urinating, painful menstruation, and abnormal menstrual bleeding

-Failure of some organs, flu-like symptoms, increased sensitivity to heat and cold, chest pressure sensation, 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 hair growth

-Thirst, dizziness, chest pressure sensation, 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.

Keep Prografout of the sight and reach of children.

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

Do not usethis medicationafter the expiration date that appears 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 the 1-year period after opening the aluminum pouch.

This medication does not require special storage conditions.

Store in the original packaging to protect it from moisture.

Medicines should not be disposed of through drains or inthe trash. Disposeof the containers and medicines that you do not need at the SIGREcollection pointat the pharmacy. If in doubt, ask your pharmacist how to dispose of the containers and medicines that you do not need. By doing so, you will help protect the environment.

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 components are:

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

Capule coating: titanium dioxide (E 171), iron oxide yellow (E 172), gelatin.

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

Prograf 1 mg hard capsules

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

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

Capule coating: titanium dioxide (E 171), gelatin.

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

Prograf 5 mg hard capsules

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

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

Capule coating: titanium dioxide (E 171), iron oxide red (E 172), gelatin.

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

Appearance of the product and contents of the package

Prograf 0.5 mg hard capsules

Yellowish white opaque capsules printed in red with “0.5 mg” and “[f] 607” containing white powder.

Prograf 0.5 mg hard capsules are presented in blisters or in pre-cut single-dose blisters with 10 capsules inside a protective aluminum bag, which includes a desiccant that protects the capsules from humidity. Do not swallow the desiccant.

Available packaging sizes are 20, 30, 50, 60 and 100 hard capsules in blisters, and 20, 30, 50, 60 and 100 hard capsules in single-dose blisters.

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 presented in blisters or in pre-cut single-dose blisters with 10 capsules inside a protective aluminum bag, which includes a desiccant that protects the capsules from humidity. Do not swallow the desiccant.

Available packaging sizes are 20, 30, 50, 60, 90 and 100 hard capsules in blisters, and 20, 30, 50, 60, 90 and 100 hard capsules in single-dose blisters.

Prograf 5 mg hard capsules

Greyish red opaque capsules printed in white with “5 mg” and “[f] 657” containing white powder.

Prograf 5 mg hard capsules are presented in blisters or in pre-cut single-dose blisters with 10 capsules inside a protective aluminum bag, which includes a desiccant that protects the capsules from humidity. Do not swallow the desiccant.

Available packaging sizes are 30, 50, 60 and 100 hard capsules in blisters, and 30, 50, 60 and 100 hard capsules in single-dose blisters.

Only some packaging sizes may be marketed.

Marketing authorization holder and responsible manufacturer

Marketing authorization holder:

Astellas Pharma, S.A.

Paseo de la Castellana, 259 D - Floor 31

28046 Madrid (Spain)

Responsible manufacturer:

Astellas Ireland Co. Limited

Killorglin

County Kerry, V93FC86

Ireland

This medicinal product 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.

Last review date of this leaflet:February 2025

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