TACROLIMUS STADA 0.5 mg HARD CAPSULES

2. What you need to know before you take Tacrolimus Stada

Do not take Tacrolimus Stada

• If you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 6).
• If you are allergic to sirolimus or any antibiotic belonging to the subgroup of macrolide antibiotics (e.g. erythromycin, clarithromycin, josamycin).

Warnings and precautions

Consult your doctor or pharmacist before starting Tacrolimus Stada.

• You will need to take tacrolimus 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 tacrolimus, your doctor may want to perform tests from time to time (including blood and urine tests, heart function tests, visual and neurological tests). This is completely normal and will help your doctor decide on the most suitable dose of tacrolimus 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 tacrolimus you need to receive. If you are in doubt, please consult your doctor before taking any plant-based 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 tacrolimus 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 tacrolimus 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 tacrolimus, using adequate 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 tacrolimus 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 fatigue, confusion, yellowing of the skin or eyes, decreased urine output, loss of vision, and convulsions (see section 4). When tacrolimus is taken 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 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 Tacrolimus Stada

Inform 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.

Tacrolimus should not be taken with cyclosporin.

If you need to visit a different doctor from 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 tacrolimus may be changed due to other medicines you are taking, and the blood levels of other medicines may be changed by the administration of tacrolimus, which may require interruption, increase, or decrease of the dose of tacrolimus.

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

The effect on blood levels of tacrolimus may occur soon after starting to use another medicine, so it may be necessary to monitor the blood level of tacrolimus frequently and continuously during the first 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 using or have recently used medicines with active ingredients such as:

• antifungals and antibiotics, especially the so-called macrolide antibiotics used to treat infections, e.g. ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid, and flucloxacillin
• letermovir, used to prevent diseases caused by CMV (human cytomegalovirus)

• HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), the pharmacokinetic enhancer cobicistat, and combination tablets, or non-nucleoside reverse transcriptase inhibitors for HIV (efavirenz, etravirine, nevirapine), used to treat HIV infection.
• HCV protease inhibitors (e.g. telaprevir, boceprevir, and 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 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. 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 arrhythmia (irregular heartbeat)
• medicines known as "statins" used to treat high cholesterol and triglycerides
• antiepileptic medicines carbamazepine, phenytoin, or phenobarbital
• metamizole, a medicine used to treat pain and fever.
• corticosteroids prednisone and methylprednisolone,
• the antidepressant nefazodone

• plant-based preparations containing St. John's Wort (Hypericum perforatum) or extracts of Schisandra sphenanthera.
• cannabidiol (uses include treatment of seizures).

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 your 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 your blood levels of tacrolimus and make necessary adjustments to the dose of tacrolimus after starting treatment for hepatitis C.

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 may worsen kidney or nervous system problems when given at the same time as tacrolimus.

Inform your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken 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 certain potassium-sparing diuretics used for heart failure, high blood pressure, and kidney disease (e.g. amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim or cotrimoxazole, which may increase potassium levels in the blood, certain painkillers (so-called NSAIDs, e.g. ibuprofen) used for fever, inflammation, and pain, anticoagulants (blood thinners), or oral medicines for the treatment of diabetes, while taking tacrolimus.

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

Taking Tacrolimus Stada with food and drinks

Take tacrolimus on an empty stomach or 2 to 3 hours after a meal. Wait at least one hour until the next meal. Avoid grapefruit (also in juice) while being treated with tacrolimus, as it may affect your levels.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Tacrolimus passes into breast milk. Therefore, you should not breastfeed while receiving tacrolimus.

Driving and using machines

Do not drive or use tools or machines if you feel dizzy or drowsy, or have problems seeing clearly after taking this medicine. These effects are more common if you also drink alcohol.

Tacrolimus Stada contains lactose and sodium

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 23 mg of sodium (1 mmol) per capsule; this is essentially "sodium-free".

3. How to take Tacrolimus Stada

Follow exactly the instructions of administration of this medicine given to you by your doctor or pharmacist. In case of 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 medicine with tacrolimus.

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 just 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 blood tests regularly to determine the correct dose and to adjust the dose from time to time. Your doctor will usually reduce your dose of tacrolimus once your condition has stabilized. Your doctor will tell you exactly how many capsules to take and how often.

Tacrolimus is taken orally, twice a day, usually in the morning and at night. In general, you should take the tacrolimus capsules on an empty stomach or at least one hour before, or 2 to 3 hours after a meal. The capsules should be swallowed whole with a glass of water. Avoid grapefruit and grapefruit juice while taking the tacrolimus capsules. Do not ingest the desiccant included in the aluminum blister.

If you take more Tacrolimus Stada than you should

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately, or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medicine and the amount ingested. It is recommended to bring the packaging and the leaflet of the medicine to the healthcare professional.

If you forget to take Tacrolimus Stada

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

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

If you stop taking Tacrolimus Stada

Stopping your treatment 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 medicine, 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.

Tacrolimus reduces the body's defense mechanism to prevent rejection of the transplanted organ. Consequently, the body will not work as well as usual in fighting infections. Therefore, if you are taking tacrolimus, you will be more prone to infections, such as skin, mouth, stomach, and intestine, lung, and urinary tract infections.

Some infections can be severe or life-threatening and may include infections caused by bacteria, viruses, fungi, parasites, or other infections. Inform your doctor immediately if you experience signs of an infection, including:

• fever, cough, sore throat, feeling of weakness or general malaise
• memory loss, difficulty thinking, difficulty walking, or loss of vision: these may be due to a rare and severe brain infection, which can be life-threatening (progressive multifocal leukoencephalopathy or PML)

Severe adverse effects may occur, including those listed below.

Inform your doctor immediately if you suspect you are experiencing 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

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

• thrombotic microangiopathy (lesions in small blood vessels) including hemolytic uremic syndrome, a condition with the following symptoms: low or no urine production (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and abnormal bruising or bleeding and signs of infection

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

• thrombocytopenic purpura (a condition that 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 production), loss of vision, and seizures.
• toxic epidermal necrolysis: erosion and blisters on the skin or mucous membranes, red swollen skin that can 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 blisters on the skin, mouth, eyes, and genitals, hives, tongue swelling, red or purple rash that spreads, skin peeling

• Torsade 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
• cases of pure red cell aplasia (a very severe reduction in red blood cell count), hemolytic anemia (decrease 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 of cold in hands and feet.
• cases of agranulocytosis (a significant decrease in white blood cell count, accompanied by mouth ulcers, fever, and infection(s)) have been reported. You may not have symptoms or you may feel sudden fever, chills, and sore throat
• allergic and anaphylactic reactions with the following symptoms: sudden itchy rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which can 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 disturbances. 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 visual field

The following adverse effects may also occur after receiving tacrolimus 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
• abnormalities in liver function tests
• diarrhea, nausea
• kidney problems

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

• decrease in blood cell count (platelets, red blood cells, or white blood cells), increase in white blood cell count, changes in red blood cell count (see blood test)

• 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 salts

• symptoms of anxiety, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders
• seizures, changes in consciousness, tingling and numbness (sometimes painful) of hands and feet, dizziness, decreased ability to write, nervous system disorders

• increased sensitivity to light, eye disorders

• ringing in the ears
• decrease in blood flow in the heart vessels, faster heart rate

• bleeding, partial or complete blockage of blood vessels, decrease in blood pressure
• difficulty breathing, changes in the respiratory tract, asthma
• intestinal obstruction, increase in blood amylase level, reflux of stomach contents into the throat, delayed stomach emptying
• dermatitis, sensation of burning 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, increase in blood lactate dehydrogenase level, weight loss

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

• small bleeding spots on the skin due to blood clots
• increase in muscle stiffness

• blindness
• deafness
• fluid accumulation around the heart

• acute difficulty breathing
• formation of cysts in the pancreas

• problems with blood flow in the liver

• severe disease with blisters on the skin, mouth, eyes, and genitals, increased hair growth
• thirst, falls, feeling of pressure in the chest, decreased mobility, ulcers

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

• muscle weakness

• abnormal echocardiogram
• liver failure, narrowing of the bile duct

• pain when urinating with blood in the urine
• increase in fatty tissue

Adverse effects of unknown frequency(cannot be estimated from available data)

• optic nerve damage (optic neuropathy)

Reporting of 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 leaflet. You can also report them through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Tacrolimus Stada

Keep this medicine out of the sight and reach of children.

Store below 30°C.

Store in the original packaging (inside the aluminum bag) to protect it from moisture and light.

Do not use this medicine after the expiration date stated on the packaging and blister after EXP. The expiration date is the last day of the month indicated. Once the aluminum bag is opened, the medicine must be used within a year.

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. 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 Tacrolimus Stada

Tacrolimus Stada 0.5 mg hard capsules EFG

The active ingredient is tacrolimus.

Each capsule contains 0.5 mg of tacrolimus.

The other ingredients are:

• Capsule content: Povidone K-30, sodium croscarmellose (E-468), lactose, magnesium stearate.
• Capsule shell: titanium dioxide (E-171), yellow iron oxide (E-172), gelatin.

Tacrolimus Stada 1 mg hard capsules EFG

The active ingredient is tacrolimus.

Each capsule contains 1 mg of tacrolimus.

The other ingredients are:

• Capsule content: Povidone K-30, sodium croscarmellose (E-468), lactose, magnesium stearate.

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

Appearance and packaging size of the product

Tacrolimus Stada 0.5 mg hard capsules EFG

Hard capsules with ivory-colored cap and body containing white powder.

Tacrolimus Stada 1 mg hard capsules EFG

Hard capsules with white-colored cap and body containing white powder.

Tacrolimus Stada is presented as blister strips containing 10 capsules inside a protective aluminum bag that includes a desiccant to protect the capsules from moisture. The desiccant should not be swallowed.

Tacrolimus Stada is available in blister packs containing 10 capsules each. Packs of 30, 50, 60, 100, and 150 capsules.

Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer

Marketing authorization holder

Laboratorio STADA, S.L.

Frederic Mompou 5

08960 Sant Just Desvern (Barcelona)

Spain

[email protected]

Manufacturer

Laboratorios Cinfa, S.A.

Olaz-Chipi, 10

Polígono Industrial Areta (Huarte-Pamplona (Navarra)) - 31620

Spain

or

STADA Arzneimittel AG

Stadastrasse 2-18

D-61118 (Bad Vilbel)

Germany

or

Eurogenerics, N.V.

Heizel Esplanade, b22 (Brussels) - 1020

Belgium

This medicine is authorized in the EEA Member States under the following names:

Germany Tacro-cell 0.5 mg/1 mg hard capsules

Spain Tacrolimus Stada 0.5 mg/1 mg hard capsules EFG

Date of last revision of this leaflet:April 2023

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