ROLTISA 0.5 mg PROLONGED-RELEASE HARD CAPSULES

Introduction

Package Leaflet: Information for the Patient

Roltisa 0.5 mg prolonged-release hard capsules EFG

Roltisa 1 mg prolonged-release hard capsules EFG

Roltisa 3 mg prolonged-release hard capsules EFG

Roltisa 5 mg prolonged-release hard capsules EFG

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.
• 1. 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 experience 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 and other information

1. What is Roltisa and what is it used for
2. What you need to know before you take Roltisa
3. How to take Roltisa
4. Possible side effects

5 Storage of Roltisa

1. Contents of the pack and further information

1. What is Roltisa and what is it used for

Roltisa contains the active substance tacrolimus. It is an immunosuppressant. After your organ transplant (liver, kidney), your body's immune system will try to reject the new organ. Roltisa is used to control your body's immune response, allowing it to accept the transplanted organ.

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

Roltisa is used in adults.

2. What you need to know before you take Roltisa

Do not take Roltisa

• 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 and Roltisa both contain the active substance tacrolimus. However, Roltisa is taken once a day, while tacrolimus immediate-release capsules are taken twice a day. This is because Roltisa capsules allow for prolonged release (slower release over a longer period) of tacrolimus.

Roltisa and tacrolimus immediate-release capsules are notinterchangeable.

Consult your doctor or pharmacist before starting Roltisa

• if you are taking any other medicine (mentioned below in “Using Roltisa with other medicines”)
• 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”.

Please avoid taking any herbal preparations, e.g. St. John's Wort (Hypericum perforatum) or any other plant-based product, as this may affect the effectiveness and dose of Roltisa 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 Roltisa.

You should stay in regular contact with your doctor. From time to time, to establish the correct dose of Roltisa, 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 Roltisa. 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:

During preparation, avoid contact with any part of the body, such as skin or eyes, as well as breathing near the injection solutions, powder, or granules contained in the tacrolimus products. If such contact occurs, wash the skin and eyes.

Children and adolescents

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

Other medicines and Roltisa

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.

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

If you need to visit a different doctor from your transplant specialist, tell the doctor that you are taking tacrolimus. Your doctor may need to consult your transplant specialist if you need to use another medicine that could increase or decrease your blood level of tacrolimus.

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

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

• antifungal and antibiotic medicines, especially macrolide antibiotics, used to treat infections, e.g. ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid, and flucloxacillin
• letermovir, used to prevent diseases caused by CMV (human cytomegalovirus)
• HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), the pharmacokinetic enhancer cobicistat, and non-nucleoside reverse transcriptase inhibitors (e.g. 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 acidity
• 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
• 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
• plant-based medicines containing St. John's Wort (Hypericum perforatum) 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 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 adjustments to your Roltisa dose 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 Roltisa.

Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, high blood pressure, and nephropathy (e.g. amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim and cotrimoxazole, which can increase potassium levels in your blood, non-steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation, and pain, anticoagulants (which prevent blood clotting), or oral medicines for the treatment of diabetes, while taking Roltisa.

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

Taking Roltisa with food and drink

Avoid grapefruit (also in juice) while being treated with Roltisa, 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 or pharmacist for advice before taking this medicine.

Roltisa passes into breast milk. Therefore, you should not breast-feed while taking this medicine.

Driving and using machines

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

Roltisa contains lactose

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

Roltisa contains red allura lake aluminum lacquer (E129)

It may cause allergic reactions.

3. How to take Roltisa

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 every time you collect your prescription, unless your transplant specialist has agreed to change to another tacrolimus medicine. This medicine should be taken once a day. 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 kg body weight and per day

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

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

After starting treatment with Roltisa, 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 Roltisa dose once your condition has stabilized. Your doctor will tell you exactly how many capsules to take.

You will need to take Roltisa every day until you continue to need immunosuppression to prevent rejection of your transplanted organ. You should stay in regular contact with your doctor.

Roltisa is taken orally once a day, in the morning. Take Roltisa 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 Roltisa than you should

If you accidentally take more Roltisa than you should, contact your doctor or go to the emergency department of the nearest hospital immediately.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medicine and the amount ingested.

If you forget to take Roltisa

If you have forgotten to take your Roltisa capsules in the morning, take them as soon as possible the same day. Do not take a double dose the next morning to make up for the forgotten doses.

If you stop taking Roltisa

Stopping your treatment with Roltisa 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.

Roltisa reduces the body's defense mechanisms (immune system), which will not work as well when fighting infections. Therefore, if you are taking Roltisa, you will be more prone to suffering from 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 tacrolimus.

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

Common 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.

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

• 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 bruising or abnormal bleeding and signs of infection.

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

• Thrombotic thrombocytopenic purpura (or TTP), 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).
• Toxic epidermal necrolysis: erosion and blistering of the skin or mucous membranes, reddened 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, peeling of the skin.
• 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.

Adverse effects with 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 colorations or changes in existing ones, lesions, or lumps.
• Cases of pure red cell aplasia (a very severe reduction in red blood cell count), hemolytic anemia (reduction in the number of red blood cells due to abnormal rupture of these cells accompanied by fatigue), and febrile neutropenia (a decrease in the type of white blood cells that fight infections, accompanied by fever). 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 decrease in the number of white blood cells accompanied by sores in the mouth, fever, and infection(s)). 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 (optic nerve disorder): vision problems such as blurred vision, changes in color vision, difficulty seeing details, or reduced visual field.

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

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

• Increased blood sugar, diabetes mellitus, increased potassium in the blood
• Difficulty sleeping
• Tremors, headache
• Increased blood pressure
• Abnormalities in liver function tests
• Diarrhea, nausea
• Kidney problems

Common adverse effects(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)
• Reduced 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)
• Anxiety symptoms, confusion and disorientation, depression, mood changes, nightmares, hallucinations, mental disorders
• Seizures, disorders of the level 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
• 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 sunburn
• Joint disorders
• Difficulty urinating, 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

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

• Changes in blood coagulation, reduction in the number of all types of blood cells (see blood test)
• Dehydration
• Reduced protein or sugar in the blood, increased phosphate in the blood
• Coma, cerebral bleeding, stroke, paralysis, cerebral 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 limb vein, 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 sunburn
• Joint disorders
• Difficulty urinating, 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 adverse effects(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 blistering of the skin, mouth, eyes, and genitals, increased hairiness
• Thirst, falls, feeling of chest stiffness, decreased mobility, ulcer

Very rare adverse effects(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 type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Roltisa

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

Do not use this medicine after the expiration date that appears on the packaging after "EXP". The expiration date is the last day of the month indicated. Use all hard prolonged-release capsules within 12 months of opening the aluminum bag.

Store below 30°C.

Medicines should not be disposed of via wastewater or household waste. Deposit the packaging and medicines you no longer need at the pharmacy's SIGRE point. If in doubt, ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Roltisa Composition

• The active ingredient is tacrolimus

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

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

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

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

• The other ingredients are:

Capsule content: ethylcellulose, butylhydroxytoluene, hypromellose, lactose monohydrate, magnesium stearate.

Capsule shell: gelatin, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172).

Printing ink: Shellac, red Allura aluminum lacquer (E129), propylene glycol (E1520), titanium dioxide (E171)

Product Appearance and Package Contents

Roltisa 0.5 mg hard prolonged-release capsules EFG are hard gelatin capsules of size 5, with an opaque yellow cap and an opaque orange body, with a length of 11.2±0.5mm, with "0.5 mg" printed on the cap in red ink.

Roltisa 0.5 mg is available in transparent PVC/PE/PVDC-Aluminum blister packs or in precut unit-dose blisters within an aluminum wrapper that includes an incorporated desiccant in the film layer. Packages of 30, 50, and 100 hard prolonged-release capsules in blisters or in precut unit-dose blisters of 30x1, 50x1, and 100x1 hard prolonged-release capsules are available.

Roltisa 1 mg hard prolonged-release capsules EFG are hard gelatin capsules of size 4, with an opaque white cap and an opaque orange body, with a length of 14.1±0.5mm, with "1 mg" printed on the cap in red ink.

Roltisa 1 mg is available in transparent PVC/PE/PVDC-Aluminum blister packs or in precut unit-dose blisters within an aluminum wrapper that includes an incorporated desiccant in the film layer. Packages of 30, 50, 60, and 100 hard prolonged-release capsules in blisters or in precut unit-dose blisters of 30x1, 50x1, 60x1, and 100x1 hard prolonged-release capsules are available.

Roltisa 3 mg hard prolonged-release capsules EFG are hard gelatin capsules of size 1, with an opaque orange cap and an opaque orange body, with a length of 19.1±0.5mm, with "3 mg" printed on the cap in red ink.

Roltisa 3 mg is available in transparent PVC/PE/PVDC-Aluminum blister packs or in precut unit-dose blisters within an aluminum wrapper that includes an incorporated desiccant in the film layer. Packages of 30, 50, and 100 hard prolonged-release capsules in blisters or in precut unit-dose blisters of 30x1, 50x1, and 100x1 hard prolonged-release capsules are available.

Roltisa 5 mg hard prolonged-release capsules EFG are hard gelatin capsules of size 0, with an opaque gray-red cap and an opaque orange body, with a length of 21.4±0.5mm, with "5 mg" printed on the cap in red ink.

Roltisa 5 mg is available in transparent PVC/PE/PVDC-Aluminum blister packs or in precut unit-dose blisters within an aluminum wrapper that includes an incorporated desiccant in the film layer. Packages of 30, 50, and 100 hard prolonged-release capsules in blisters or in precut unit-dose blisters of 30x1, 50x1, and 100x1 hard prolonged-release capsules are available.

Not all package sizes may be marketed

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Pharmathen S.A.

6 Dervenakion str.,

Pallini, 15351 Attiki

Greece

Manufacturer

Pharmathen S.A.

Dervenakion 6

Pallini 15351

Attiki,

Greece

Or

Pharmathen International S.A.

Industrial Park Sapes,

Rodopi Prefecture,

Block No 5,

Rodopi 69300,

Greece

This medicine is authorized in the Member States of the European Economic Area under the following names:

Denmark: Roltisa

Germany: Roltisa 0.5mg, 1mg, 3mg & 5mg prolonged release hard capsules

Spain: Roltisa 0.5mg, 1mg, 3mg and 5mg hard prolonged-release capsules EFG

Greece: Roltisa

Date of the last revision of this leaflet:April 2025

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