TACFORIUS 1 mg PROLONGED-RELEASE HARD CAPSULES

2. What you need to know before you take Tacforius

Do not take Tacforius

• 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 macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin).

Warnings and precautions

Tacrolimus immediate-release capsules (e.g. Tacni) and Tacforius prolonged-release capsules both contain the active substance tacrolimus. However, Tacforius prolonged-release capsules are taken once daily, while immediate-release capsules are taken twice daily. This is because Tacforius capsules allow for prolonged release (slower release over a longer period) of tacrolimus. Tacforius prolonged-release capsules and tacrolimus immediate-release capsules are not interchangeable.

Consult your doctor or pharmacist before starting Tacforius:

• if you are taking any other medicines (mentioned below in "Other medicines and Tacforius")
• if you have or have had liver problems
• if you have had diarrhea for more than one day
• if you feel strong abdominal pain accompanied by other symptoms such as chills, fever, nausea, or vomiting
• if you have an alteration in the electrical activity of your heart called "prolonged QT interval".
• if you have or have had damage to the small blood vessels, known as thrombotic microangiopathy/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, vision loss, and seizures (see section 4). When tacrolimus is taken with sirolimus or everolimus, the risk of these symptoms may increase.

Please avoid taking any herbal preparations, e.g. St. John's Wort (Hypericum perforatum) or any other herbal products, as this may affect the effectiveness and dose of Tacforius you need to receive. If you have any doubts, please consult your doctor before taking any herbal products or preparations.

Your doctor may need to adjust your dose of Tacforius.

You should stay in regular contact with your doctor. From time to time, to establish the correct dose of Tacforius, your doctor may need to perform blood and urine tests, heart tests, eye tests.

You should limit your exposure to sunlight and UV (ultraviolet) while taking Tacforius. This is because immunosuppressants can increase the risk of skin cancer. Wear protective clothing and use a sunscreen with a high sun protection factor.

Handling precautions:

Avoid contact with any part of the body, such as skin or eyes, as well as breathing in the powder contained in the capsules. If such contact occurs, wash the skin and eyes.

Children and adolescents

Tacforius is not recommended for use in children and adolescents under 18 years of age.

Other medicines and Tacforius

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

Tacforius should not be used with cyclosporin (another medicine used to prevent organ transplant rejection).

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.

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

Some patients have experienced increases in tacrolimus blood levels 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 Tacforius blood levels can occur soon after starting to use another medicine, so it may be necessary to monitor the blood level of Tacforius 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 recently taken medicines such as:

• antifungals and antibiotics, especially macrolide antibiotics, used to treat infections, e.g. ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid, and flucloxacillin
• letermovir, used to prevent diseases caused by CMV (human cytomegalovirus)
• HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), the pharmacoenhancer cobicistat, and combination tablets, 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 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)
• cisapride or the antacid magnesium-aluminum hydroxide, used to treat heartburn
• the contraceptive pill or other hormonal treatments with ethinylestradiol, hormonal treatments with danazol
• medicines used to treat high blood pressure or heart problems (e.g. 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
• carbamazepine, phenytoin, or phenobarbital, used to treat epilepsy
• cannabidiol (its use includes, among others, the treatment of epileptic seizures)
• metamizole, used to treat pain and fever
• corticosteroids prednisolone or methylprednisolone, belonging to the class of corticosteroids used to treat inflammation or suppress the immune system (e.g. transplant rejection)
• nefazodone, used to treat depression
• herbal products containing St. John's Wort (Hypericum perforatum) or extracts of Schisandra sphenanthera.

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

Tell your doctor if you are taking or need to take ibuprofen (used to treat fever, inflammation, and pain), antibiotics (cotrimoxazole, vancomycin, or aminoglycoside antibiotics such as gentamicin), amphotericin B (used to treat fungal infections), or antivirals (used to treat viral infections, e.g. acyclovir, ganciclovir, cidofovir, foscarnet). These medicines may worsen kidney or nervous system problems when taken with Tacforius.

Tell your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken with sirolimus or everolimus, the risk of thrombotic microangiopathy, 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 diuretics used for heart failure, high blood pressure, and kidney disease (e.g. amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim and cotrimoxazole, which may increase potassium levels in your blood, non-steroidal anti-inflammatory medicines (NSAIDs, e.g. ibuprofen) used for fever, inflammation, and pain, anticoagulants (which prevent blood clotting), or oral medicines for diabetes treatment, while taking Tacforius.

If you are planning to get vaccinated, consult your doctor.

Taking Tacforius with food and drinks

Avoid grapefruit (also in juice) while you are being treated with Tacforius, as it may affect your blood levels.

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 for advice before taking this medicine.

Tacrolimus passes into breast milk. Therefore, you should not breast-feed while taking Tacforius.

Driving and using machines

Do not drive or use tools or machines if you feel dizzy or sleepy, or have problems seeing clearly after taking Tacforius. These effects are more frequent if you also drink alcohol.

Tacforius contains lactose

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

Tacforius 5 mg capsules contain Ponceau 4R

This may cause allergic reactions.

3. How to take Tacforius

Follow exactly the administration instructions of this medicine given by your doctor. In case of doubt, consult your doctor or pharmacist again. This medicine should only be prescribed by a doctor with experience in the treatment of patients with transplants.

Make sure you receive the same medicine with tacrolimus each time you collect your prescription, unless your transplant specialist has agreed to change to another tacrolimus medicine. This medicine should be taken once daily. If the appearance of this medicine is not the same as usual, or if the dosing 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 daily initial doses just after transplant will generally be within the range of

0.10 - 0.30 mg per kilogram of body weight and per day

depending on the transplanted organ. To treat rejection, these same doses may be used.

Your dose depends on your overall condition and any other immunosuppressive medication you may be taking.

After starting treatment with Tacforius, your doctor will perform frequent blood tests to determine the correct dose. Afterward, 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 decrease your dose of Tacforius once your condition has stabilized. Your doctor will tell you exactly how many capsules to take.

You will need to take Tacforius every day as long as you need immunosuppression to prevent rejection of your transplanted organ. You should stay in regular contact with your doctor.

Tacforius is taken orally once daily, in the morning. Take Tacforius on an empty stomach or 2 to 3 hours after a meal. Wait at least one hour until the next meal. Take the capsules immediately after removing them from the blister pack. The capsules should be swallowed wholewith a glass of water.

Do not swallow the desiccant contained in the aluminum bag.

If you take more Tacforius than you should

If you accidentally take too many capsules, contact your doctor or go to the emergency department of the nearest hospital.

If you forget to take Tacforius

If you miss taking your capsules in the morning, take them as soon as possible on the same day. Do not take a double dose the next morning.

If you stop taking Tacforius

Stopping your treatment with Tacforius 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 medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people will experience them.

Tacforius reduces the body's defense mechanisms (immune system), which will not work as well to fight infections. Therefore, if you are taking Tacforius, you will be more prone to infections.

Some infections can be serious 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 serious brain infection (progressive multifocal leukoencephalopathy or PML)

Severe effects can occur, including allergic reactions and anaphylaxis. Benign and malignant tumors have been reported after treatment with Tacforius.

Inform your doctor immediately if you suspect you are experiencing any of the following serious adverse effects:

Frequent Serious 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 Serious Adverse Effects(may affect up to 1 in 100 people):

• Microangiopathic thrombosis (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 abnormal bleeding or signs of infection.

Rare Serious 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 can 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 can peel off in large areas of the body.
• Blindness.

Very Rare Serious 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, skin peeling.
• 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.

Serious 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 significant reduction in red blood cell count), hemolytic anemia (reduction in red blood cell count due to abnormal breakdown), and febrile neutropenia (reduction 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 reduction in white blood cell count accompanied by mouth sores, fever, and infection(s)) have been reported. 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 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 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 (damage to the optic nerve): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.

After receiving Tacforius, the following adverse effects may also occur and may be serious:

Very Frequent(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
• Abnormal liver function tests
• Diarrhea, nausea
• Kidney problems

Frequent(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)
• Reduction of 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 (see blood test)
• Symptoms of anxiety, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders
• Seizures, disorders of consciousness, tingling and numbness (sometimes painful) in hands and feet, dizziness, decreased ability to write, nervous system disorders
• Increased sensitivity to light, eye disorders
• Ringing in the ears
• Reduced blood flow in the heart vessels, faster heart rate
• Bleeding, partial or complete blockage of blood vessels, decreased blood pressure
• Shortness of breath, respiratory tract disorders, asthma
• Intestinal obstruction, increased blood level of amylase enzyme, reflux of stomach contents into the throat, delayed emptying of the stomach
• Skin inflammation, sensation of burning in the sun
• Joint disorders
• Inability to urinate, painful and abnormal menstrual bleeding
• Multi-organ failure, catarrhal disease, increased sensitivity to heat and cold, feeling of pressure in the chest, restlessness or abnormal feeling, increased lactate dehydrogenase enzyme in the blood, weight loss

Less Frequent(may affect up to 1 in 100 people)

• Changes in blood coagulation, reduction in all types of blood cells (see blood test)
• Dehydration
• Reduction of proteins or sugar in the blood, increased phosphate in the blood
• Coma, cerebral bleeding, stroke, paralysis, brain disorders, speech and language disorders, memory problems
• Cataract
• Hearing impairment
• Irregular heartbeat, cardiac arrest, decreased heart performance, heart muscle disorders, increased heart muscle size, stronger heartbeat, abnormal ECG, abnormal heart rate and pulse
• Blood clot in a vein of a limb, shock
• Breathing difficulties, respiratory tract disorders, asthma
• Intestinal obstruction, increased blood level of amylase enzyme, reflux of stomach contents into the throat, delayed emptying of the stomach
• Skin inflammation, sensation of burning in the sun
• Joint disorders
• Inability to urinate, painful and abnormal menstrual bleeding
• Multi-organ failure, catarrhal disease, increased sensitivity to heat and cold, feeling of pressure in the chest, restlessness or abnormal feeling, increased lactate dehydrogenase enzyme in the blood, weight loss

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

• Small skin bleeding due to blood clots
• Increased muscle stiffness
• Deafness
• Fluid accumulation around the heart
• Acute shortness of breath
• Pancreatic cyst formation
• Problems with blood flow in the liver
• Severe disease with blistering of the skin, mouth, eyes, and genitals; increased hairiness
• Thirst, falls, feeling of stiffness in the chest, decreased mobility, ulcers

Very Rare(may affect up to 1 in 10,000 people)

• Muscle weakness
• Abnormal cardiac ultrasound
• Liver failure
• Painful urination, with blood in the urine
• Increased fatty tissue

Reporting of Adverse Effects

If you experience any adverse effects, consult your doctor or pharmacist, even if they are possible adverse effects not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Tacforius

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

Do not use this medicine after the expiration date stated on the carton and blister after "EXP". The expiration date is the last day of the month indicated.

Store in the original packaging to protect from light and moisture. This medicine does not require any special storage temperature.

Use all hard prolonged-release capsules within the year following the opening of the aluminum packaging.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Tacforius

• The active ingredient is tacrolimus.

Each 0.5 mg Tacforius capsule contains 0.5 mg of tacrolimus (as monohydrate).

Each 1 mg Tacforius capsule contains 1 mg of tacrolimus (as monohydrate).

Each 3 mg Tacforius capsule contains 3 mg of tacrolimus (as monohydrate).

Each 5 mg Tacforius capsule contains 5 mg of tacrolimus (as monohydrate).

• The other ingredients are:

Capsule content

Hypromellose 2910, ethylcellulose, lactose, magnesium stearate.

Capsule shell

Tacforius 0.5 mg/1 mg/3 mg hard prolonged-release capsules EFG:

red iron oxide (E172), yellow iron oxide (E172), titanium dioxide (E171), gelatin

Tacforius 5 mg hard prolonged-release capsules EFG:

red iron oxide (E172), yellow iron oxide (E172), titanium dioxide (E171), black iron oxide (E172), Ponceau 4R (E124), gelatin

Printing ink

Shellac, propylene glycol, black iron oxide (E172), potassium hydroxide

Appearance of the Product and Package Contents

Tacforius 0.5 mg hard prolonged-release capsules EFG

Hard gelatin capsules printed with "TR" on the light yellow capsule shell and with "0.5 mg" on the light orange capsule body.

Tacforius 1 mg hard prolonged-release capsules EFG

Hard gelatin capsules printed with "TR" on the white capsule shell and with "1 mg" on the light orange capsule body.

Tacforius 3 mg hard prolonged-release capsules EFG

Hard gelatin capsules printed with "TR" on the light orange capsule shell and with "3 mg" on the light orange capsule body.

Tacforius 5 mg hard prolonged-release capsules EFG

Hard gelatin capsules printed with "TR" on the gray-red capsule shell and with "5 mg" on the light orange capsule body.

Tacforius 0.5 mg/3 mg/5 mg hard prolonged-release capsules EFG

Supplied as blisters or unit dose blisters with 10 capsules inside an aluminum protective bag, which includes a desiccant. Available in packs of 30, 50, and 100 prolonged-release capsules in blisters and packs of 30x1, 50x1, and 100x1 prolonged-release capsules in unit dose blisters.

Tacforius 1 mg hard prolonged-release capsules EFG

Supplied as blisters or unit dose blisters with 10 capsules inside an aluminum protective bag, which includes a desiccant. Available in packs of 30, 50, 60, and 100 prolonged-release capsules in blisters and packs of 30x1, 50x1, 60x1, and 100x1 prolonged-release capsules in unit dose blisters.

Marketing Authorization Holder

Teva B.V.

Swensweg 62

2031 GA Haarlem

Netherlands

Manufacturer

Merckle GmbH

Ludwig-Merckle-Straße 3

89143 Blaubeuren

Germany

PLIVA Hrvatska d.o.o.

Prilaz baruna Filipovica 25

10 000 Zagreb

Croatia

Teva Czech Industries s.r.o.

Ostravská 29, c.p. 305

Opava-Komárov

74770

Czech Republic

Teva Operations Poland Sp. z.o.o.

Mogilska 80

31-546 Krakow

Poland

Teva Pharma S.L.U.

C/C, n. 4, Polígono Industrial Malpica,

ES-50016 Zaragoza

Spain

TEVA Pharmaceutical Works Private Limited Company

Pallagi út 13

4042 Debrecen

Hungary

You can obtain more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet:

Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu/.