Prospecto:information for the patient

Envarsus 0.75mg prolonged-release tablets

Envarsus 1mg prolonged-release tablets

Envarsus 4mg prolonged-release tablets

tacrolimus

Read this prospectus carefully before starting to take this medicine, as it contains important information for you.

• Keep this prospectus, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.

-This medicine has been prescribed only for you, and you must not give it to other people even if they have the same symptoms as you, as it may harm them.

• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this prospectus.See section 4.

1.What Envarsus is and for what it is used

2.What you need to know before starting to take Envarsus

3.How to take Envarsus

4.Possible adverse effects

5.Storage of Envarsus

6.Contents of the pack and additional information

Envarsuscontains the active ingredient tacrolimus. It is an immunosuppressant. After undergoing a kidney or liver transplant, your immune system will attempt to reject the new organ.

Envarsusis used to control your body's immune response to allow it to accept the transplanted organ.

It may also be prescribed for Envarsus to treat rejection occurring in your liver, kidney, heart, or other transplanted organ, in the event that previous treatment has not controlled this immune response after your transplant.

Envarsusis used for treatment in adults.

Do not take Envarsus

-if you are allergic to tacrolimus or any of the other components of this medication (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 ingredient tacrolimus presented in a prolonged-release formulation.Envarsus is taken once a day andcannot be interchanged with other medications containing tacrolimus (immediate or prolonged release) at an equivalent dose.

Consult your doctor or pharmacist before starting to take Envarsus if:

• you have or have had liver problems;
• you have had diarrhea for more than a day.
• you are taking any of the medications listed in the section «Other medications and Envarsus»;
• you have a heart rhythm disorder called «prolongation of the QT».

• severe abdominal pain accompanied or not by other symptoms, such as chills, fever, nausea, or vomiting;
• an infection that leads to kidney problems or neurological symptoms;
• headache, alteration of mental state, convulsions, and visual disturbances;
• weakness, change in skin or eye color, easy bruising, infection, cough, anemia;
• you have or have had small blood vessel injuries, known as microangiopathic hemolytic anemia/thrombotic thrombocytopenic purpura/syndrome hemolytic uremic. Inform your doctor if you develop fever, skin hematomas (may appear as red spots), unexplained fatigue, confusion, yellowing of the skin or eyes, decreased urine output, vision loss, and convulsions (see section4). When tacrolimus is taken with sirolimus or everolimus, the risk of these symptoms may increase.

Please avoid taking any herbal preparations, p.eg., St. John's Wort (Hypericum perforatum) or any other herbal product, as this may affect the effectiveness and dose of Envarsus 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 Envarsus dose or decide to interrupt the tacrolimus treatment.

You must maintain regular contact with your doctor. From time to time, your doctor may need to perform tests or blood, urine, heart, or eye analyses to determine the appropriate Envarsus dose.

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

Children and adolescents

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

Other medications and Envarsus

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication, including over-the-counter medications and herbal products.

Envarsus is not recommended to be taken 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 blood levels of Envarsus may be affected by other medications you take and vice versa, the blood levels of other medications may be affected by the taking of Envarsus, which may require the interruption, increase, or decrease of the Envarsus dose.

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

The effect on Envarsus blood levels can occur very soon after starting to use another medication, so you may need to monitor your Envarsus 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 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 human cytomegalovirus (CMV)
• protease inhibitors for HIV (e.g., ritonavir, nelfinavir, saquinavir), the potentiator cobicistat, and combined tabletsor non-nucleoside reverse transcriptase inhibitors for HIV (efavirenz, etravirine, nevirapine)used to treat HIV infection
• protease inhibitors for HCV (e.g., telaprevir, boceprevir, the combination ofombitasvir/paritaprevir/ritonavir with or without dasabuvir,elbasvir/grazoprevir, and glecaprevir/pibrentasvir), used to treat hepatitisC
• nilotinib and imatinib,idelalisib, crizotinib, apalutamide, enzalutamide, or mitotane(used to treat certain cancers)
• mycophenolic acid, used to suppress the immune system to prevent transplant rejection
• medications used 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 antacids containing aluminum and magnesium hydroxide, used to treat heartburn
• 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)
• antiarrhythmics (e.g., amiodarone) used to control irregular heartbeats
• statins, used to treat elevated cholesterol and triglycerides
• carbamazepine, phenytoin, or phenobarbital, used to treat epilepsy
• metamizole, used to treat pain and fever
• steroidsprednisolone 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
• herbal products containing hypericum (St. John's Wort) or extracts ofSchisandra sphenanthera
• cannabidiol (its use includes, among others, the treatment of epilepsy)

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

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), orantivirals(used to treat viral infections, e.g., acyclovir, ganciclovir, cidofovir, foscarnet).These medications may worsen kidney or nervous system problems if taken with Envarsus.

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 will also need to know if you are taking potassium supplements or certain diuretics used to treat heart failure, high blood pressure, and nephropathy (e.g., amiloride, triamterene, or spironolactone), or trimethoprim or cotrimoxazole antibiotics, which may increase your potassium levels in the blood, nonsteroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen) used to treat fever, inflammation, and pain, anticoagulants, or oral medications for diabetes.

Inform your doctor in advance if you need to receive any vaccine.

Envarsus with food and drinks

Avoid taking grapefruit (or its juice) while receiving Envarsus treatment, as it may affect the concentration of this medication in the blood.

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

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

Driving and operating machinery

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

Envarsus contains lactose

Envarsus contains lactose (milk sugar).

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

If your doctor has told you that you have a certain sugar intolerance, consult with him before taking this medication.

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 experienced doctors in the treatment of transplant patients.

Important information

Ensure that the same tacrolimus-based medication is administered to you every time you pick up your prescription, unless your transplant specialist has agreed to change your medication for another one.

This medication should only be taken once a day. If the appearance of this medication is not as usual, or if the administration instructions for the dose have changed, consult your doctor or pharmacist as soon as possible to ensure you are taking the correct medication.

How much Envarsus do I have to take

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

The initial daily doses immediately after the transplant will generally fall within the following range0.11‑0.17mg per day per kg of body weight, depending on which organ was transplanted.It is possible that the same doses will 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 medication, your doctor will perform frequent blood tests to determine the correct dose. You will then have regular blood tests to allow your doctor to define the correct dose and adjust it. Your doctor will generally reduce your Envarsus dose once your condition has stabilized.

How do I take Envarsus tablets

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

Take the tablets immediately after removing them from the blister pack. The tablets should be swallowedwholewith the help of a glass of water. Do not swallow the desiccant included in the aluminum packaging.

How long do I have to take Envarsus tablets

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

If I take more Envarsus than I should

If you accidentally take an excessive dose of Envarsus, contact your doctor or the nearest hospital emergency department immediately.

If I forget to take Envarsus

Do not take a double dose to compensate for the missed doses. Take the tabletas soon as possible on the same day.

If I interrupt Envarsus treatment

Stopping Envarsus treatment may increase the risk of organ rejection.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.

Tacrolimus reduces the body's defense mechanism (the immune system), making it less able to fight off infections. Therefore, you may be more prone to infections while takingEnvarsus.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 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 [PML])

Immediately contact your doctor if you experience severe side effects.

Severe side effects may include allergic reactions and anaphylaxis. Cases of benign and malignant tumors have been reported after treatment with Envarsus.

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):

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

• Microangiopathic thrombosis (lesions in smaller blood vessels) including hemolytic uremic syndrome with the following symptoms:low or no urine output (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and abnormal bleeding or bruising, and signs of infection.

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

• Purpura thrombocytopenic thrombocytopenia:includes lesions in smaller blood vessels and is characterized by fever and bleeding under the skin that may appear as red spots, with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), with symptoms of acute kidney failure (low or no urine output), vision loss, and seizures.
• Toxic epidermal necrolysis: skin erosion and blistering, red and swollen skin that may peel off in large areas of the body.
• Blindness.

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

• Stevens-Johnson syndrome: inexplicable generalized skin pain, facial swelling, severe illness with blistering of the skin, mouth, eyes, and genitals, rashes, facial swelling, skin peeling.
• Torsades de pointes: a change in heart rhythm that may or may not be accompanied by symptoms such as chest pain (angina), fainting, dizziness, nausea, palpitations (feeling heartbeats), and difficulty breathing.

Severe side effects of unknown frequency:

• Oportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.
• Cases of benign and malignant tumors have been reported as a result of immunosuppression, including malignant skin cancers and a rare type of cancer that may include skin lesions known as Kaposi's sarcoma. Symptoms include skin changes such as new colors or changes to existing ones, lesions, or lumps.
• Cases of 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 cells that fight infections, accompanied by fever). The exact frequency of these side effects is unknown. You may not have symptoms or, depending on the severity of your condition, you may feel: fatigue, apathy, pale skin (pallor), difficulty breathing, dizziness, headache, chest pain, and a sensation of coldness in your hands and feet.
• Cases of agranulocytosis (a significant decrease in white blood cells accompanied by mouth sores, fever, and infection). 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 hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and feeling 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.

After receiving Envarsus, the following side effects may also occur and may be severe:

Very common side 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
• Renal problems

Common side 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 white blood cells, changes in red blood cell count (observed in blood tests)
• Reduction in magnesium, phosphate, potassium, calcium, or sodium levels in the blood, fluid overload (hypervolemia), increase in blood sugar levels or lipids, decrease in appetite, loss of appetite, increase in blood acidity, other changes in blood electrolytes (observed in blood tests)
• Anxiety symptoms, confusion, and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders
• Seizures, altered consciousness, tingling and numbness (sometimes painful) in hands and feet, dizziness, coordination disorders, nervous system disorders
• Increased sensitivity to light, eye disorders
• Tinnitus in the ears
• Reduction in blood flow to the heart's blood vessels, acceleration of heartbeats
• Bleeding, partial or complete blockage of blood vessels, decrease in blood pressure
• Dyspnea, changes in lung tissue, fluid accumulation around the lung, pharyngitis, cough, pseudogripal symptoms
• Inflammatory or ulcerative conditions causing abdominal pain or diarrhea, gastric hemorrhage, inflammatory or ulcerative oral conditions, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, meteorism, soft stools, gastrointestinal problems
• Biliary disorders, yellowing of the skin due to liver problems, liver tissue damage, and inflammation of the liver
• Pruritus, skin rash, hair loss, acne, increased sweating
• Joint pain, limb, or back pain, muscle cramps
• Renal insufficiency, reduced urine production, altered urination, or painful urination
• General weakness, fever, fluid accumulation in the body, pain, and discomfort, increased alkaline phosphatase levels in the blood, weight gain, altered body temperature sensation

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

• Changes in blood clotting, 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 proteins or sugar, increase in blood phosphates
• Coma, cerebral hemorrhage, apoplexy, paralysis, cerebral disorders, speech and language disorders, memory problems
• Opacity of the crystalline lens, total or partial loss of hearing
• Irregular heartbeats, cardiac arrest, reduced heart function, myocardial disorders, increased heart size, stronger heartbeats, changes in electrocardiogram, changes in heart rate and pulse
• Thrombosis in a vein of a limb, shock
• Dyspnea, respiratory tract disorders, asthma
• Acute or chronic pancreatitis, inflammatory condition of the abdominal wall lining, intestinal obstruction, increased amylase levels in the blood, gastroesophageal reflux, delayed defecation
• Skin inflammation, sensitivity to sunlight
• Joint disorders
• Inability to urinate, painful menstruation, and abnormal menstrual bleeding
• Multi-organ failure, pseudogripal disease, increased sensitivity to heat and cold, chest pressure, numbness or strange sensation, increased lactate dehydrogenase levels in the blood, weight loss

Rare side 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 dyspnea
• Formation of pancreatic cysts, pre-obstructive intestinal condition
• Problems with liver blood flow
• Severe illness with skin blistering, mouth, eyes, and genitals
• Increased hair growth
• Thirst, falls, chest tightness, immobility, ulcers

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

• Muscle weakness
• Auditory disorders
• Changes in cardiac explorations
• Liver insufficiency
• Painful urination, with blood in the urine
• Increased body fat

Reporting side effects:

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through theSistema Español de Farmacovigilancia de Medicamentos de Uso Humanohttps://www.notificaRAM.es. 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, blister pack, and wrapper after «EXP».The expiration date is the last day of the month indicated.

Do not store at a temperature above 25°C

Store within the original aluminum packaging to protect it from light.

Use all prolonged-release tablets within 45 days of opening 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 you no longer need. This will help protect the environment.

Composition of Envarsus

• The active ingredient is tacrolimus.

Envarsus 0.75mg prolonged-release tablets

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

Envarsus 1mg prolonged-release tablets

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

Envarsus 4mg prolonged-release tablets

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

• The other components are hypromellose, lactose monohydrate, macrogol 6000, poloxamer 188, magnesium stearate, tartaric acid (E334), butylated hydroxytoluene (E321), and dimethicone 350.

Appearance of the product and contents of the pack

The prolonged-release tablets of Envarsus 0.75mg are oval in shape, white to off-white in color, and have the text «0.75» on one face and «TCS» on the other.

The prolonged-release tablets of Envarsus 1mg are oval in shape, white to off-white in color, and have the text «1» on one face and «TCS» on the other.

The prolonged-release tablets of Envarsus 4mg are oval in shape, white to off-white in color, and have the text «4» on one face and «TCS» on the other.

Envarsusis supplied in PVC/Al blisters containing 10tablets.Three blisters are packaged together in an aluminum protective wrapper with desiccant. Envarsus is available in pack sizes of 30, 60, and 90 prolonged-release tablets.

Only some pack sizes may be marketed.

Marketing Authorization Holder

Chiesi Farmaceutici S.p.A.

Via Palermo, 26/A

43122 Parma

Italy

Responsible Person

Rottendorf Pharma GmbH

Ostenfelder Straβe 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 Vienna

Austria

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

Last update of this leaflet: February 2025

Other sources of information

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