Envarsus 1mg PROLONGED-RELEASE TABLETS

Introduction

Package Leaflet:information for the patient

Envarsus 0.75mg prolonged-release tablets

Envarsus 1mg prolonged-release tablets

Envarsus 4mg prolonged-release tablets

tacrolimus

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

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

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

Contents of the pack

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

1. What is Envarsus and what is it used for

Envarsus contains the active substance tacrolimus. It is an immunosuppressant. After you have had a kidney or liver transplant, your immune system will try to reject the new organ.

Envarsus is used to control your body’s immune response to allow the transplanted organ to be accepted.

It may also be given to you if you are having a rejection of your liver, kidney, heart or other transplanted organ and a previous treatment has not controlled this immune response after your transplant.

Envarsus is used for treatment in adults.

2. What you need to know before you take Envarsus

Do not take Envarsus

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

Warnings and precautions

Envarsus contains the active substance tacrolimus in a prolonged-release formulation. Envarsus is taken once daily and must notbe switched with other medicines containing tacrolimus (immediate- or prolonged-release) with an equivalent dose.

Consult your doctor or pharmacist before starting Envarsus if:

• you have or have had liver problems;
• you have had diarrhea for more than one day.
• you are taking any of the medicines listed under ‘Other medicines and Envarsus’;
• you have a heart condition called ‘QT prolongation’.

• a severe abdominal pain accompanied by or without other symptoms such as chills, fever, nausea or vomiting;
• an infection leading to kidney problems or neurological symptoms;
• headache, altered mental status, seizures and visual disturbances;
• weakness, change in skin or eye color, easy bruising, infection, cough, anemia;
• you have or have had damage to 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 dots), unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urine output, loss of vision 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 plant-based products, as this may affect the effectiveness and the dose of Envarsus you need to receive. If you are in doubt, please consult your doctor before taking any plant-based product or preparation.

Your doctor may need to adjust your dose of Envarsus or decide to stop treatment with tacrolimus.

You should keep in regular contact with your doctor. From time to time, your doctor may need to carry out tests or blood, urine, heart or eye tests to determine the correct dose of Envarsus.

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

Children and adolescents

The use of Envarsus is not recommended in children and adolescents below 18 years.

Other medicines and Envarsus

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

It is not recommended to take Envarsus with ciclosporin (another medicine used to prevent organ rejection).

If you need to see a different doctor, tell them 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 blood level of tacrolimus.

The blood levels of Envarsus can be affected by other medicines you take and vice versa, the blood levels of other medicines can be affected by the taking of Envarsus, which may require interruption, increase or decrease of the dose of Envarsus.

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

The effect on blood levels of Envarsus can occur very soon after starting to use another medicine, so it may be necessary to monitor the blood level of Envarsus 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 can increase the risk of organ rejection. In particular, you should inform your doctor if you are taking or have recently taken medicines such as:

• antifungals and antibiotics, especially those known as 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 booster cobicistat and the 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, the combination of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir), used to treat hepatitis C
• nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide or mitotane (used to treat certain cancers)
• mycophenolic acid, used to suppress the immune system to prevent transplant rejection
• medicines to treat stomach ulcers and acid reflux (e.g. omeprazole, lansoprazole or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
• cisapride or the antacid aluminium and magnesium 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)
• antiarrhythmics (e.g. 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
• metamizole, used to treat pain and fever
• corticosteroids prednisolone and methylprednisolone, belonging to the class of corticosteroids and used to treat inflammation or to suppress the immune system (e.g. in case of transplant rejection)
• nefazodone, used to treat depression
• plant-based medicines containing hypericum (St. John’s Wort) or extracts of Schisandra sphenanthera
• cannabidiol (its use includes, among others, the treatment of epileptic seizures)

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

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. aciclovir, ganciclovir, cidofovir, foscarnet). These medicines may worsen kidney or nervous system problems if taken with Envarsus.

Tell 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).

While taking Envarsus, your doctor will also need 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 or cotrimoxazole, which can increase the potassium levels in your blood, non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen) used to treat fever, inflammation and pain, anticoagulants or oral medicines for diabetes.

Tell your doctor in advance if you need to receive any vaccination.

Taking Envarsus with food and drinks

Avoid taking grapefruit (or its juice) while being treated with Envarsus, as it may affect the levels of this medicine in your blood.

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. A study evaluated the outcomes of pregnancy in women treated with tacrolimus and other immunosuppressants. Although this study did not provide enough evidence to draw conclusions, higher rates of spontaneous abortion were reported among liver and kidney transplant patients treated with tacrolimus, as well as higher rates of persistent hypertension, associated with protein loss in the urine, among kidney transplant patients that develop during pregnancy or the postpartum period (a condition called preeclampsia). No increased risk of serious congenital anomalies was found with the use of Envarsus.

Tacrolimus passes into breast milk. Therefore, you must not breast-feed while taking Envarsus.

Driving and using machines

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

Envarsus contains lactose

Envarsus contains lactose (milk sugar).

• Envarsus 0.75 mg tablets: 41.7 mg
• Envarsus 1 mg tablets: 41.7 mg
• Envarsus 4 mg tablets: 104 mg

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

3. How to take Envarsus

Always take this medicine exactly as your doctor has told you. If you are not sure, check with your doctor or pharmacist.

This medicine should only be prescribed by doctors with experience in the treatment of transplant patients.

Important information

Make sure that you always receive the same tacrolimus-based medicine each time you collect your prescription, unless your transplant specialist has agreed to switch you to a different one.

This medicine should only be taken once daily. If the appearance of this medicine is not the usual one, or the dosing instructions have changed, consult your doctor or pharmacist as soon as possible to make sure you are taking the correct medicine.

How much Envarsus to take

Your doctor will determine your initial dose based on your body weight to prevent rejection of your transplanted organ.

The initial daily doses immediately after transplantation are generally within the following range: 0.11-0.17 mg daily per kg body weight, depending on the transplanted organ. The same doses may be used to treat rejection.

The dose you receive will depend on your overall condition and the other immunosuppressants you are taking. After starting treatment with this medicine, your doctor will frequently carry out blood tests to determine the correct dose. Then, you will have regular blood tests to determine the correct dose and adjust it. Your doctor will generally reduce your dose of Envarsus once your condition has stabilized.

How to take the Envarsus tablets

Envarsus is taken orally once daily, usually on an empty stomach.

Take the tablets immediately after removal from the blister. The tablets should be swallowed wholewith a glass of water. Do not swallow the desiccant included in the aluminum foil.

How long to take the Envarsus tablets

You will need to take Envarsus daily while you need immunosuppression to prevent rejection of your transplanted organ. You should keep in regular contact with your doctor.

If you take more Envarsus than you should

If you accidentally take too much Envarsus, contact your doctor or the emergency department of your nearest hospital immediately.

If you forget to take Envarsus

Do not take a double dose to make up for forgotten doses. Take the tablet as soon as possible on the same day.

If you stop taking Envarsus

Stopping treatment with Envarsus 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 action of the body's defense mechanism (the immune system), which will make it lose its ability to fight infections. Consequently, you may be more prone to suffering from infections while taking Envarsus. 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 [PML])

Contact your doctor immediately if you experience severe effects.

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

Tell your doctor immediately if you suspect you are suffering from 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 your transplanted organ.
• Blurred vision.

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

• Microangiopathic thrombocytopenia (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 signs of infection.

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

• Thrombotic thrombocytopenic purpura: includes lesions in smaller 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 illness 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, including malignant skin cancers and a rare type of cancer that can include skin lesions known as Kaposi's sarcoma. Symptoms include skin changes such as new colors or changes in existing ones, lesions, or lumps.
• Cases of pure red cell aplasia (a significant reduction in red blood cell count), hemolytic anemia (reduction in the number of red blood cells due to abnormal breakdown, 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 with which these adverse effects occur is not known. You may not have symptoms or, depending on the severity of the conditions, you may feel: fatigue, apathy, abnormal paleness of the skin (pallor), difficulty breathing, dizziness, headache, chest pain, and a feeling of cold in hands and feet.
• Cases of agranulocytosis (a significant decrease in the number of white blood cells, accompanied by mouth sores, fever, and infection). You may not have symptoms or you may suddenly feel 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 Envarsus, the following adverse effects can also occur and may be serious:

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

• Increased blood sugar or potassium levels, diabetes mellitus
• Difficulty falling asleep
• Tremors, headache
• Increased blood pressure
• Changes in liver function tests
• Diarrhea, nausea
• Kidney problems

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

• Reduction in the number of certain blood cells (platelets, red blood cells, or white blood cells), increase in the number of white blood cells, changes in the number of red blood cells (observed in blood tests)
• Reduction in blood magnesium, phosphate, potassium, calcium, or sodium levels, fluid overload (hypervolemia), increased blood uric acid or lipid levels, decreased appetite, loss of appetite, increased blood acidity, other changes in blood salts (observed in blood tests)
• 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, disorder of writing ability, changes in the nervous system
• Increased sensitivity to light, eye disorders
• Ringing in the ears
• Reduced blood flow to the heart's blood vessels, increased heart rate
• Bleeding, partial or complete blockage of blood vessels, decreased blood pressure
• Shortness of breath, respiratory tract disorders, asthma
• Acute or chronic pancreatitis, inflammation of the lining of the abdominal wall, intestinal obstruction, increased blood amylase levels, reflux of stomach contents into the throat, delayed bowel movement
• Skin inflammation, sensitivity to sunlight
• Joint disorders
• Inability to urinate, painful and abnormal menstrual bleeding
• Multi-organ failure, flu-like illness, increased sensitivity to heat and cold, feeling of pressure in the chest, nervousness or strange feeling, increased blood lactate dehydrogenase levels, weight loss

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

• Changes in blood coagulation, reduction in the number of all types of blood cells (observed in blood tests)
• Dehydration
• Psychotic behavior, such as delusional ideas, hallucinations, and confusion
• Reduction in blood protein or sugar levels, increased blood phosphate levels
• Coma, cerebral hemorrhage, stroke, paralysis, brain disorder, speech and language disorders, memory problems
• Cataract, complete or partial inability to hear
• Irregular heartbeats, cardiac arrest, reduced heart function, myocardial disorder, increased heart size, stronger heartbeats, changes in electrocardiogram, changes in heart rate and pulse
• Blood clot in a limb vein, shock
• Difficulty breathing, respiratory tract disorders, asthma
• Acute or chronic pancreatitis, inflammation of the abdominal wall lining, intestinal obstruction, increased blood amylase levels, reflux of stomach contents into the throat, delayed bowel movement
• Skin inflammation, sensitivity to sunlight
• Joint disorders
• Inability to urinate, painful and abnormal menstrual bleeding
• Multi-organ failure, flu-like illness, increased sensitivity to heat and cold, feeling of pressure in the chest, nervousness or strange feeling, increased blood lactate dehydrogenase levels, weight loss

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

• Small skin hemorrhages due to blood clots
• Increased muscle stiffness
• Deafness
• Fluid accumulation around the heart
• Acute difficulty breathing
• Pancreatic cyst formation, pre-intestinal obstruction state
• Liver blood flow problems
• Severe illness with blistering of the skin, mouth, eyes, and genitals
• Increased hair growth
• Thirst, falls, feeling of chest tightness, loss of mobility, ulcer

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

• Muscle weakness
• Hearing disorders
• Changes in cardiac examinations
• Liver failure
• Painful urination, with blood in the urine
• Increased fatty tissue

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 not listed in this leaflet. You can also report them directly through the Spanish Medicines Agency's website for human use: https://www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Envarsus

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

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

Do not store above 25°C.

Store in the original aluminum packaging to protect from light.

Use all prolonged-release tablets within 45 days of opening the aluminum packaging.

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

6. Package contents and additional information

Composition of Envarsus

• The active ingredient is tacrolimus.

Envarsus 0.75 mg prolonged-release tablets

Each prolonged-release tablet contains 0.75 mg of tacrolimus (as monohydrate).

Envarsus 1 mg prolonged-release tablets

Each prolonged-release tablet contains 1 mg of tacrolimus (as monohydrate).

Envarsus 4 mg prolonged-release tablets

Each prolonged-release tablet contains 4 mg of tacrolimus (as monohydrate).

• The other ingredients are hypromellose, lactose monohydrate, macrogol 6000, poloxamer 188, magnesium stearate, tartaric acid (E334), butylhydroxytoluene (E321), and dimeticone 350.

Appearance and packaging of the product

Envarsus 0.75 mg prolonged-release tablets are oval, white to beige in color, and engraved with "0.75" on one side and "TCS" on the other.

Envarsus 1 mg prolonged-release tablets are oval, white to beige in color, and engraved with "1" on one side and "TCS" on the other.

Envarsus 4 mg prolonged-release tablets are oval, white to beige in color, and engraved with "4" on one side and "TCS" on the other.

Envarsus is supplied in PVC/Al blisters containing 10 tablets. 3 blisters are packaged together in a protective aluminum wrapper with a desiccant. Packs of 30, 60, and 90 prolonged-release tablets are marketed.

Not all pack sizes may be marketed.

Marketing authorization holder

Chiesi Farmaceutici S.p.A.

Via Palermo, 26/A

43122 Parma

Italy

Manufacturer

Rottendorf Pharma GmbH

Ostenfelder Straße 51 - 61

59320 Ennigerloh

Germany

or

Chiesi Farmaceutici S.p.A.

Via San Leonardo 96

43122 Parma

Italy

or

Chiesi Pharmaceuticals GmbH

Gonzagagasse 16/16

1010 Wien

Austria

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

Date of last revision of this leaflet: February 2025

Other sources of information

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