Patient Information Leaflet

Tacforius 0.5mg prolonged-release hard capsules EFG

Tacforius 1mg prolonged-release hard capsules EFG

Tacforius 3mg prolonged-release hard capsules EFG

Tacforius 5mg prolonged-release hard capsules EFG

tacrolimus

Read this leaflet carefully before you start taking this medicine, as it contains important information for you.

• Keep this leaflet, aspossibly you will need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only, anddo 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 leaflet. See section4.

1. What isTacforiusand what it is used for

2. What you need to know before starting to takeTacforius

3. How to takeTacforius

4. Possible side effects

5. Storage ofTacforius

6. Contents of the pack and additional information

Tacforius contains the active ingredient tacrolimus. It is an immunosuppressant. After an organ transplant (liver, kidney), the immune system of your body will attempt to reject the new organ. Tacforius is used to control the immune response of your body, allowing you to accept the transplanted organ.

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

Tacforiusis used in adults.

Do not take Tacforius

-if you are allergic to tacrolimus or any of the other components of this medication (listed in section6).

-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 ingredient tacrolimus. However, Tacforius prolonged-release capsules are taken once a day, while immediate-release capsules are taken twice a day. This is because Tacforius prolonged-release capsules allow for prolonged release (slower release over a longer period of time) of tacrolimus. Tacforius prolonged-release capsules and tacrolimus in immediate-release capsules are not interchangeable.

Consult your doctor or pharmacist before starting to take Tacforius:

• if you are taking any medication (listed below in “Other medications and Tacforius”)
• if you have or have had liver problems
• if you have had diarrhea for more than a day
• if you have a strong abdominal pain accompanied or not by other symptoms, such as chills, fever, nausea, or vomiting
• if you have a heart rhythm disorder called “prolongation of the QT interval”.
• if you have or have had small blood vessel injuries, known as microangiopathic hemolytic anemia/thrombotic thrombocytopenic purpura/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.

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

Your doctor may need to adjust your Tacforius dose.

You should maintain regular contact with your doctor.From time to time, to establish the appropriate dose ofTacforius, your doctor may need to perform blood and urine tests, cardiac tests, eye tests.

You should limit your exposure to sunlight and UV (ultraviolet) while takingTacforius. This is because immunosuppressants may increase the risk of skin cancer. Wear protective clothing and use a high-factor sunscreen.

Precautions for handling:

Avoid contact with any part of the body, such as the skin or eyes, as well as breathing near 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 18years.

Other medications and Tacforius

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

Tacforius should not be used with cyclosporine (another medication used to prevent organ transplant rejection).

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 medication that may increase or decrease your tacrolimus blood levels..

The Tacforius blood levels may be affected by other medications you are taking, and the blood levels of other medications may be affected by the administration of Tacforius, which may require the interruption, increase, or decrease of the Tacforius dose.

Some patients have experienced increases in tacrolimus blood levels while taking other medications.This could cause severe adverse effects, such as kidney problems, nervous system problems, and heart rhythm disorders (see section4).

The effect on Tacforius blood levels can occur very soon after starting to use another medication, so it may be necessary to monitor Tacforius blood levels frequently and continuously during the first days of use of another medication and frequently while continuing its use.Some other medications may cause tacrolimus blood levels to decrease, which may increase the risk of organ transplant rejection.Particularly, you should inform your doctor if you are taking or have taken recently medications 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 human cytomegalovirus (CMV)

-protease inhibitors for HIV (e.g., ritonavir, nelfinavir, saquinavir), the pharmacopotentiator cobicistat, and combined tablets, 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 hepatitis C infection

-nilotinib and imatinib, ,idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane(used to treat certain types of cancer)

-micophenolic acid, used to suppress the immune system as a transplant rejection prevention

-medications for stomach ulcers and acid reflux (e.g., omeprazole, lansoprazole, or cimetidine)

-antiemetics, used to treat nausea and vomiting (e.g., metoclopramide)

-cisapride or antacids containing magnesium hydroxide and aluminum, used to treat acid reflux

-oral contraceptives or other hormone treatments with ethinylestradiol, hormone treatments with danazol

-medications used to treat high blood pressure or heart problems (e.g., nifedipine, nicardipine, diltiazem, and verapamil)

-antiarrhythmic medications (amiodarone) used to control irregular heartbeats

-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 seizures)

-metamizole, used to treat pain and fever

-steroid corticosteroids, such as prednisolone or methylprednisolone, 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 Schisandra sphenanthera extracts.

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 tacrolimus blood levels. Tacrolimus blood levels may decrease or increase depending on the medications prescribed for hepatitis C. Your doctor may need to closely monitor your tacrolimus blood levels and make the necessary adjustments to the Tacforius dose after starting hepatitis C treatment.

Inform 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., aciclovir, ganciclovir, cidofovir, foscarnet).These medications may worsen kidney or nervous system problems when taken with Tacforius.

Inform your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken with sirolimus or everolimus, the risk of microangiopathic hemolytic anemia, 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 diuretics used to treat heart failure, hypertension, and nephropathy (e.g., amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim and cotrimoxazole that may increase your potassium levels in the blood,nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen) used to treat fever, inflammation, and pain,anticoagulants (which prevent blood clotting), or oral medications for diabetes treatment while taking Tacforius.

If you plan to be vaccinated, consult your doctor.

Taking Tacforius with food and drinks

Avoid grapefruit (also in juice) while taking Tacforius, as it may affect your blood levels.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, or plan to become pregnant, consult your doctor before using this medication.

Tacrolimus passes into breast milk. Therefore, do not breastfeed while taking Tacforius.

Driving and operating machinery

Do not drive and do not operate tools or machines if you feel dizzy or drowsy, or have difficulty seeing clearly after taking Tacforius. These effects are more frequent if you also take alcohol.

Tacforius contains lactose

If your doctor has told you that you have intolerance to certain sugars, consult with them before taking this medication.

Tacforius 5mg capsules contain Ponceau 4R

This may cause allergic reactions.

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

Make sure you receive the same medication with tacrolimus every time you pick up your prescription, unless your transplant specialist has agreed to switch to another medication different from tacrolimus. This medication should be taken once 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 according to your body weight. The initial daily doses immediately after the transplant will generally be within the range of

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

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

Your dose will depend on your general condition, and any other immunosuppressive medication you may be taking.

After starting your treatment with Tacforius, your doctor will perform frequent blood tests to define the correct dose. After that, your doctor will need to perform regular blood tests to define the correct dose, and to adjust the dose from time to time. Your doctor will usually reduce your Tacforius doseonce your conditions have stabilized. Your doctor will tell you exactly how many capsules you should take.

You will need to takeTacforiusevery day until you no longer need immunosuppression to prevent rejection of your transplanted organ. You should maintain regular contact with your doctor.

Tacforius is taken orally once a day, in the morning. Take Tacforius with an empty stomach or2 to3hours after a meal.Wait at least one hour before the next meal.Take the capsules immediately after removing them from the blister pack.The capsules should be swallowedwholewith 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 nearest hospital emergency department.

If you forget to take Tacforius

If you have forgotten to take 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 interrupt treatment with Tacforius

Stopping your treatment withTacforius 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 doubts about the use of this medication, ask your doctor or pharmacist.

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

Tacforius reduces the body's defense mechanisms (immune system), which will not work as well to fight off infections. Therefore, if you are taking Tacforius, you will be more prone to getting 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 weak or generally unwell
• Memory loss, difficulty 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 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 severe side effects:

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

Less common severe side effects (may affect up to 1 in 100 people):(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.

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

• Purpura thrombocytopenic thrombosis: includes lesions in smaller blood vessels and is characterized by fever and bruising under the skin that may appear as red spots, with or without extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), with symptoms of acute kidney failure (low or no urine output), vision loss, 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):(may affect up to 1 in 10,000 people)

• Sjögren's syndrome: inexplicable generalized skin pain, facial swelling, severe illness with blistering of the skin, mouth, eyes, and genitals, rashes, facial swelling, and peeling of the skin.
• 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 the heartbeat), and difficulty breathing.

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

• Infections: diarrhea, fever, and sore throat.
• Benign and malignant tumors have been reported after treatment with Tacforius as a result of immunosuppression.
• 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 white blood cell count that fights infections, accompanied by fever). The exact frequency of these side effects is unknown. You may not have symptoms or, depending on the severity, you may feel: fatigue, apathy, pale skin (pallor), difficulty breathing, dizziness, headache, chest pain, and a feeling of coldness in the hands and feet.
• Agranulocytosis (a significant decrease in white blood cell count accompanied by mouth sores, fever, and infections). You may not have symptoms or may feel fever, chills, and sudden sore throat.
• Allergic reactions and anaphylaxis with the following symptoms: sudden itching rash (hives), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing) and may feel like you are going to faint.
• Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood changes, seizures, and visual disturbances. These may be signs of a condition known as posterior reversible encephalopathy 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.Details

After receivingTacforiusyou may also experience the following side effects, which can be severe:

Very common (may affect more than 1 in 10 people):(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
• Renal problems

Common (may affect up to 1 in 10 people):(may affect up to 1 in 10 people)

• Reduction in the number of blood cells (platelets, red blood cells, or white blood cells), increased white blood cell count, changes in red blood cell counts (see blood test)
• Reduction in 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 electrolytes (see blood test)
• Anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders
• Seizures, disorders of consciousness, tingling and numbness (sometimes painful) in the hands and feet, dizziness, decreased ability to write, nervous system disorders
• Increased sensitivity to light, eye disorders
• Tinnitus in the ears
• Reduced blood flow in the coronary arteries, faster heart rate
• Bleeding, partial or complete blockage of blood vessels, reduced blood pressure
• Lack of breath, changes in lung tissue, fluid accumulation around the lungs, inflammation of the pharynx, cough, flu-like symptoms
• Inflammations or ulcers that cause abdominal pain or diarrhea, bleeding in the stomach, inflammation or ulcers in the mouth, fluid accumulation in the intestines, vomiting, abdominal pain, indigestion, constipation, flatulence, abdominal swelling, loose stools, gastrointestinal problems
• Biliary tract disorders, yellowing of the skin due to liver problems, liver tissue damage, and liver inflammation
• Itching, rash, hair loss, acne, increased sweating
• Pain in the joints, extremities, back, and feet, muscle spasms
• Renal insufficiency, reduced urine production, difficulty or pain when urinating
• General weakness, fever, fluid accumulation in the body, pain and discomfort, increased alkaline phosphatase in the blood, weight gain, feeling of altered temperature

Less common (may affect up to 1 in 100 people):(may affect up to 1 in 100 people)

• Coefficient changes in blood coagulation, reduction in the number of all types of blood cells (see blood test)
• Dehydration
• Reduction in blood proteins or sugar, increased phosphate in the blood
• Coma, cerebral hemorrhage, stroke, paralysis, brain disorders, speech and language abnormalities, memory problems
• Opacity of the crystalline lens
• Deterioration of hearing
• Irregular heartbeat, cardiac arrest, decreased heart function, heart muscle disorders, increased heart muscle size, faster heartbeat, abnormal ECG, abnormal heart rate and pulse
• Thrombosis of a vein in a limb, shock
• Difficulty breathing, respiratory tract disorders, asthma
• Intestinal obstruction, increased blood levels of the enzyme amylase, gastroesophageal reflux, delayed stomach emptying
• Skin inflammation, sunburn sensation
• Joint disorders
• Inability to urinate, painful menstruation, and abnormal menstrual bleeding
• Multi-organ failure, catarrhal disease, increased sensitivity to heat and cold, chest pressure sensation, restlessness or abnormal sensation, increased lactate dehydrogenase in the blood, weight loss

Rare (may affect up to 1 in 1,000 people):(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 illness with vesicle formation in the skin, mouth, eyes, and genitals; increased hair growth
• Sedation, falls, chest stiffness sensation, decreased mobility, ulcer

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

• Muscle weakness
• Abnormal echocardiogram
• Liver insufficiency
• Painful urination, blood in the urine
• Increased body fat

Reporting of side effects:

If you experienceany type of side effect, consult your doctor or pharmacist, even if it is apossibleside effect that does not appear in this leaflet.You can also report them directly through thenational reporting system included in theAppendixV. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the box and the blister pack after “EXP.”The expiration date is the last day of the month indicated.

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

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

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. In this way, you will help protect the environment.

Composition of Tacforius

• The active principle is tacrolimus.

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

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

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

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

• The other components are:

Content of the capsule

Hypromellose 2910, ethylcellulose, lactose, magnesium stearate.

Capsule coating

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

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

Tacforius 5 mg hard gelatin 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 contents of the pack

Tacforius 0.5 mg capsules

Hard gelatin capsules printed with "TR" on the yellowish clear cap of the capsule and with "0.5 mg" on the orange clear body of the capsule.

Tacforius 1 mg capsules

Hard gelatin capsules printed with "TR" on the white cap of the capsule and with "1 mg" on the orange clear body of the capsule.

Tacforius 3 mg capsules

Hard gelatin capsules printed with "TR" on the orange clear cap of the capsule and with "3 mg" on the orange clear body of the capsule.

Tacforius 5 mg capsules

Hard gelatin capsules printed with "TR" on the reddish-grey cap of the capsule and with "5 mg" on the orange clear body of the capsule.

Tacforius 0.5 mg/3 mg/5 mg capsules

Supplied as blister packs or pre-cut blister packs with 10 capsules in a protective aluminium bag, which includes a desiccant.Available in packs of 30, 50, and 100 prolonged-release capsules in blister packs and in packs of 30x1, 50x1, and 100x1 prolonged-release capsules in pre-cut blister packs.

Tacforius 1 mg capsules

Supplied as blister packs or pre-cut blister packs with 10 capsules in a protective aluminium bag, which includes a desiccant.Available in packs of 30, 50, 60, and 100 prolonged-release capsules in blister packs and in packs of 30x1, 50x1, 60x1, and 100x1 prolonged-release capsules in pre-cut blister packs.

Marketing Authorisation Holder

Teva B.V.

Swensweg 62

2031 GA Haarlem

Netherlands

Responsible Person

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

TEVAPharmaceutical Works Private Limited Company

Pallagi út 13

4042 Debrecen

Hungary

For further information about this medicinal product, please contact the local representative of the marketing authorisation holder:

Last update of this leaflet:

The detailed information on this medicinal product is available on the website of the European Medicines Agency:http://www.ema.europa.eu/.