ENVARSUS 0.75 mg Extended-release tablet

Зміст інструкції

1. Envarsus 0.75 mg prolonged-release tablets, 1 mg prolonged-release tablets, 4 mg prolonged-release tablets
   1. What is Envarsus and what is it used for
   2. What you need to know before taking Envarsus
   3. How to take Envarsus
   4. Possible side effects
   5. How to store Envarsus
   6. Package contents and other information

Envarsus 0.75 mg prolonged-release tablets, 1 mg prolonged-release tablets, 4 mg prolonged-release tablets

tacrolimus

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

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If any side effects occur, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

• 1. What Envarsus is and what it is used for
• 2. What you need to know before you take Envarsus
• 3. How to take Envarsus
• 4. Possible side effects
• 5. How to store 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 medicine. Following a
kidney or liver transplant, the body's immune system will try to reject the new organ.
Envarsus is used to control the body's immune response, allowing it to accept the transplanted
organ.
You may also receive Envarsus if a rejection of the liver, kidney, heart or other transplanted organ is
occurring, if one of the treatments you were previously taking has not been able to
control this immune response after the transplant.
Envarsus is used in adults.

2. What you need to know before taking 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 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 and is notinterchangeable with other existing medicines that
contain tacrolimus (immediate-release or prolonged-release) at the same dose.
Talk to your doctor or pharmacist before taking Envarsus:

• if you have, or have had, liver problems.
• if you have had diarrhoea for more than one day.
• if you are taking any medicine mentioned under “Other medicines and Envarsus”.
• if you have an alteration in the electrical activity of the heart called “QT prolongation”.
• if you have severe abdominal pain accompanied or not by other symptoms such as chills, fever, nausea or vomiting.
• if you have an infection that causes kidney problems or neurological symptoms.
• if you have headache, altered mental status, convulsions and vision disturbances.
• if you have weakness, altered skin or eye colour, easy bruising, infection, cough, anaemia.
• if you have or have had damage to the smallest blood vessels, known as thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Tell your doctor if you develop fever, bruising under the skin (which may appear as red dots), unexplained fatigue, confusion, yellowing of the skin or eyes, decreased urine production, vision loss, and seizures (see section 4). When tacrolimus is taken together with sirolimus or everolimus, the risk of developing these symptoms may increase.

Please avoid taking any remedies of herbal origin, such as St. John's wort (Hypericum perforatum) or any other products of herbal origin, as
it may change the effectiveness and dose of Envarsus you need to receive. If you have any doubts
please consult your doctor before taking any herbal products or remedies.
Your doctor may need to adjust your dose of Envarsus or decide to stop the
treatment with tacrolimus.
You must keep in regular contact with your doctor. From time to time, your doctor may consider it
necessary to subject you to blood tests, urine tests, heart or eye checks, to establish the
correct dose of Envarsus.
You should limit your exposure to the sun and ultraviolet (UV) light while taking Envarsus.
This is necessary because immunosuppressants can increase the risk of skin cancer.
Wear appropriate protective clothing and apply a sunscreen with a high protection factor.

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

Other medicines and Envarsus
Tell your doctor or pharmacist if you are taking, have recently taken or might take
any other medicines, including those available without a prescription and herbal remedies.
The use of Envarsus with ciclosporin (another medicine used to prevent organ rejection) is not recommended.

If you visit a doctor other than the transplant specialist, tell them that you are taking
tacrolimus. The doctor may need to consult with the transplant specialist if you
need to use another medicine that can increase or decrease tacrolimus concentrations
in the blood.
The levels of Envarsus in the blood can be affected by other medicines you are taking and
vice versa, the levels in the blood of the medicines you are taking can be affected
by taking Envarsus, which may require interruption, an increase or a decrease
of the dose of Envarsus.
Some patients have shown increases in tacrolimus concentrations in the blood while
taking other medicines. This can cause serious side effects, such as kidney problems, problems
of the nervous system and heart rhythm disturbances (see section 4).
An effect on the concentrations of Envarsus in the blood can occur very soon after the start
of using another medicine, so frequent and continuous monitoring of the concentration of Envarsus in the blood may be necessary in the first few days after starting the other medicine and
frequently during treatment with the other medicine. Some other medicines may cause
a decrease in tacrolimus concentrations in the blood, which may increase the risk of organ rejection.
In particular, you should tell your doctor if you are taking or have
recently taken medicines such as:

• antifungal and antibiotic medicines, especially so-called macrolide antibiotics, used to treat infections (e.g. ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telitromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid and flucloxacillin)
• letermovir, used to prevent a disease caused by CMV (human cytomegalovirus)
• HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), the potentiator cobicistat and combination tablets or non-nucleoside reverse transcriptase inhibitors of HIV (efavirenz, etravirine, nevirapine) used to treat HIV infection
• 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
• nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide or mitotane (used to treat certain types of cancer)
• mycophenolic acid, used to inhibit the immune system and prevent organ rejection
• medicines for stomach ulcers and acid reflux (e.g. omeprazole, lansoprazole or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
• cisapride or magnesium-aluminium-hydroxide antacid, used to treat stomach acidity (heartburn)
• birth control pills or other hormonal treatments containing ethinylestradiol, hormonal treatments with danazol
• medicines used to treat high blood pressure (hypertension) or heart problems (e.g. nifedipine, nicardipine, diltiazem and verapamil)
• anti-arrhythmic medicines (amiodarone) used to control irregular heartbeats
• the medicines called "statins", used to treat high cholesterol and triglyceride levels
• carbamazepine, phenytoin or phenobarbital, for the treatment of epilepsy
• metamizole, used for the treatment of 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 organ transplant rejection)
• nefazodone, used to treat depression
• herbal preparations containing St. John's wort (Hypericum perforatum) or extracts of Schisandra sphenanthera
• cannabidiol (uses include, also, the treatment of seizures)

Tell your doctor if you are receiving treatment for hepatitis C. Pharmacological treatment for
hepatitis C can alter liver function and affect tacrolimus concentrations in the
blood. Tacrolimus concentrations in the blood may decrease or increase depending on
the medicines prescribed for hepatitis C. Your doctor may need to carefully monitor
tacrolimus concentrations in the blood and make the necessary dose adjustments after the start
of treatment for hepatitis C.
Tell your doctor if you are taking or are about to take ibuprofen (for the treatment of fever,
inflammation and pain), antibiotics (cotrimoxazole, vancomycin or aminoglycoside antibiotics such as
gentamicin), amphotericin B (for the treatment of fungal infections) or antiviral drugs (for
the treatment of viral infections, for example acyclovir, ganciclovir, cidofovir, foscarnet). These
medicines can worsen kidney or nervous system problems when taken with Envarsus.
Tell your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken together
with sirolimus or everolimus, the risk of developing thrombotic microangiopathy, thrombotic
thrombocytopenic purpura and hemolytic uremic syndrome may increase (see section 4).
The doctor also needs to know if you, while taking Envarsus, take potassium supplements or certain diuretics used for heart failure, hypertension and kidney disease (e.g. amiloride, triamterene or spironolactone), or the antibiotics trimethoprim or cotrimoxazole which
can increase potassium levels in the blood, non-steroidal anti-inflammatory drugs (NSAIDs, e.g.
ibuprofen), used against fever, to treat inflammatory states and pain,
anticoagulants (blood thinners), or oral diabetes medicines.
If you need to be vaccinated, talk to your doctor first.

Envarsus with food and drink
Avoid grapefruit (including juice) during treatment with Envarsus, as it may affect
the levels of the medicine in the blood.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning to become pregnant or are breastfeeding,
ask your doctor for advice before taking this medicine. In one study, the outcomes of pregnancy were assessed in women treated with tacrolimus and in women treated with other
immunosuppressants. Although the evidence collected in this study is not sufficient to draw
conclusions, higher rates of miscarriage have been reported in patients receiving liver and kidney transplant and treated with tacrolimus, as well as higher rates, in patients receiving kidney transplant, of persistent hypertension associated with protein loss in the urine, which develops during
pregnancy or in the postpartum period (a condition called pre-eclampsia). No increased risk of major birth defects associated with the use of Envarsus has been detected.
Tacrolimus is excreted in breast milk. Therefore, you should not breastfeed while taking
Envarsus.

Driving and using machines
Do not drive vehicles or use tools or machines if you feel dizzy or drowsy, or if
you cannot see clearly after taking Envarsus. These effects are more common if you
also take 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, contact them before taking this medicine.

3. How to take Envarsus

Take this medicine following exactly the instructions of your doctor. If you have any doubts, ask your
doctor or pharmacist.
This medicine must be prescribed to you exclusively by a doctor with experience in the treatment
of transplant patients.

Important information
Make sure you always receive the same medicine containing tacrolimus each time you pick up your
prescription, unless your transplant specialist has agreed to switch to a different
medicine containing tacrolimus.
This medicine must be taken once a day. If the appearance of this medicine is not the
same as usual, or if the dosage instructions have changed, contact your doctor or
pharmacist as soon as possible to make sure you have received the correct medicine.

What dose of Envarsus should I take
The initial dose to prevent organ rejection will be established by your doctor and calculated
based on your body weight.
The initial daily doses, immediately after transplantation, will generally fall within the range of:
0.11 and 0.17 mg per each kg of body weight per day, depending on the transplanted organ. To treat
rejection, the same doses can be used.
Your dose depends on your general condition and which other immunosuppressant medicine you are
taking. After starting treatment with this medicine, your doctor will subject you to
frequent blood tests to determine the correct dose. Subsequently, periodic blood tests by the
doctor will be necessary to determine the correct dose and adjust it from time to time.
Usually the doctor will reduce your dose of Envarsus when your condition has stabilized.

How should I take the Envarsus tablets
Envarsus is taken orally once a day, generally on an empty stomach.
Take the tablets immediately after removing them from the blister pack. The tablets
must be swallowed wholewith a glass of water. Do not ingest the desiccant contained
in the aluminum foil wrapper.

For how long should I take the Envarsus tablets
You will have to take Envarsus every day, as long as you need immunosuppression to prevent
organ rejection. You must keep in regular contact with your doctor.

If you take more Envarsus than you should
If you have accidentally taken too much Envarsus, contact your doctor or the emergency room of the nearest
hospital immediately.

If you forget to take Envarsus
Do not take a double dose to make up for a missed tablet. 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 do so.
If you have any doubts about the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Tacrolimus reduces the defense mechanism of your body (the immune system), which will not be
as effective as before in fighting infections. Therefore, you may be more susceptible to infections
while taking Envarsus. Some infections may be serious or fatal and can include
infections caused by bacteria, viruses, fungi, parasites, or other infections.
Inform your doctor immediately if you experience signs of an infection, including:

• Fever, cough, sore throat, feeling weak or generally unwell
• Memory loss, difficulty with thinking, difficulty walking, or loss of vision - these may be due to a very rare and serious brain infection, which can be fatal (Progressive Multifocal Leukoencephalopathy or PML). If you experience severe effects, seek immediate medical attention. Serious effects, including allergic and anaphylactic reactions, may occur. Benign and malignant tumors have been reported to occur after treatment with Envarsus.

Inform your doctor immediately if you have or suspect you may have any of the following
serious side effects:
Common serious side effects(may affect up to 1 in 10 people):

• Gastrointestinal perforation: severe abdominal pain with or without other symptoms, such as chills, fever, nausea, or vomiting.
• Insufficient function of the transplanted organ.
• Blurred vision.

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

• Thrombotic microangiopathy (damage to the smallest blood vessels), including hemolytic uremic syndrome, a condition with the following symptoms: reduced or absent urine output (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and abnormal bruising (ecchymosis) or bleeding, and signs of infection.

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

• Thrombotic thrombocytopenic purpura: a condition that includes damage to the smallest blood vessels and is characterized by fever and skin bruising that may appear as red spots, with or without extreme unjustified fatigue, confusion, yellowing of the skin or eyes (jaundice), with symptoms of acute kidney failure (reduced or absent urine output), loss of vision, and seizures.
• Toxic epidermal necrolysis: erosion and blistering of the skin or mucous membranes, reddened and swollen skin that may peel off from large areas of the body.
• Blindness.

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

• Stevens-Johnson syndrome: unexplained widespread skin pain, facial swelling, severe illness with blistering of the skin, mouth, eyes, and genitals, hives, swelling of the tongue, red or purple skin rash that spreads, and 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, nausea, palpitations (strong awareness of your heartbeat), and shortness of breath.

Serious side effects – frequency not known(frequency cannot be estimated on the basis of
available data):

• Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.
• Following treatment, the occurrence of benign and malignant tumors has been reported, resulting from immunosuppression, including skin cancers and a rare type of cancer that can include skin lesions, called Kaposi's sarcoma. Symptoms include changes in the skin, such as new or changing discoloration, lesions, or nodules.
• Cases of pure red cell aplasia (a very severe decrease in red blood cell count), hemolytic anemia (reduced number of red blood cells due to their abnormal destruction accompanied by fatigue), and febrile neutropenia (a decrease in the type of white blood cells that fight infections, accompanied by fever) have been reported. It is not known exactly how often these side effects occur. It may have no symptoms, or, depending on the severity of the condition, you may experience: fatigue, apathy, abnormal paleness of the skin, shortness of breath, dizziness, headache, chest pain, and cooling of the hands and feet.

Cases of agranulocytosis (a strongly reduced number of white blood cells accompanied by mouth ulcers, fever, and infection(s)) have been reported. You may not have symptoms or may have sudden fevers, chills, and sore throat.

• Allergic and anaphylactic reactions with the following symptoms: sudden itchy skin rash (urticaria), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and you may feel weak.
• Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood swings, seizures, and visual disturbances. These may be signs of a condition called posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
• Optic neuropathy (abnormality of the optic nerve): vision problems, such as blurred vision, changes in color vision, difficulty seeing details, or restriction of the field of vision.

The following side effects may also occur after taking Envarsus and may be
serious:
Very common side effects(may affect more than 1 in 10 people):

• Increased blood sugars (glucose), diabetes mellitus, increased potassium in the blood
• Difficulty sleeping
• Tremor, headache
• Increased blood pressure
• Abnormal results of liver function tests
• Diarrhea, nausea
• Kidney problems

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

• Decreased number of blood cells (platelets, red blood cells, or white blood cells), increased levels of white blood cells, changes in red blood cell levels (emerged from blood tests)
• Decreased magnesium, phosphate, potassium, calcium, or sodium in the blood, fluid overload, increased uric acid or lipids in the blood, loss of appetite, decreased appetite, increased acidity in the blood, other changes in blood salt balance (emerged from blood tests)
• Symptoms of anxiety, confusion, and disorientation, depression, mood swings, nightmares, hallucinations, mental disorders
• Seizures, altered state of consciousness, tingling and numbness (sometimes with pain) in the hands and feet, dizziness, impaired ability to write, nervous system disorders
• Increased sensitivity to light, eye disorders
• Ringing in the ears
• Reduced blood flow in the heart vessels, increased heart rate
• Bleeding, partial or total blockage of blood vessels, decreased blood pressure
• Shortness of breath, changes in lung tissue, fluid accumulation around the lungs, inflammation of the pharynx, cough, flu-like symptoms
• Inflammation or ulcers with resulting abdominal pain or diarrhea, bleeding in the stomach, inflammation or ulcers in the mouth, fluid accumulation in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, bloating, soft stools, stomach problems
• Bile duct disorders, yellowing of the skin due to liver problems, liver tissue damage and inflammation
• Itching, skin rash, hair loss, acne, increased sweating
• Joint, limb, or back pain, muscle cramps
• Impaired kidney function, reduced urine production, impaired or painful urination
• Generalized weakness, fever, fluid accumulation in the body, pain and discomfort, increased alkaline phosphatase in the blood, weight gain, feeling of altered temperature

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

• Changes in blood coagulation, decreased number of all types of blood cells (emerged from blood tests)
• Dehydration
• Psychotic behavior such as delusions, hallucinations, and confusion
• Decreased proteins or sugar in the blood, increased phosphate in the blood
• Coma, cerebral hemorrhage, stroke, paralysis, brain disorders, abnormalities of speech and language expression, memory problems
• Cataract of the eye, partial or total inability to hear
• Irregular heartbeat, cessation of heartbeat, reduced heart performance, heart muscle disorders, enlargement of the heart muscle, stronger heartbeat, abnormalities in the electrocardiogram (ECG), abnormalities in heart rate and pulse
• Blood clot in a vein in a limb, shock
• Difficulty breathing, respiratory system disorders, asthma
• Acute or chronic inflammation of the pancreas, inflammation of the inner lining of the abdominal wall, early intestinal blockage, increased levels of amylase in the blood, reflux of stomach contents into the esophagus, delayed gastric emptying
• Skin inflammation, burning sensation with sun exposure
• Joint disorders
• Inability to urinate, painful menstruation and abnormal menstrual bleeding
• Multiorgan failure, flu-like syndrome, increased sensitivity to heat and cold, feeling of oppression in the chest, feeling of restlessness or discomfort, increased lactate dehydrogenase in the blood, weight loss

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

• Mild bleeding of the skin, caused by blood clots
• Increased muscle stiffness
• Deafness
• Fluid accumulation around the heart
• Acute respiratory failure
• Cyst formation in the pancreas, early intestinal blockage
• Problems with blood circulation in the liver
• Severe illness with blistering of the skin, mouth, eyes, and genitals
• Increased hair growth
• Thirst, falls, feeling of constriction in the chest, decreased mobility, ulcer

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

• Muscle weakness
• Impaired hearing
• Abnormal echocardiogram
• Liver failure
• Painful urination, with blood in the urine
• Increased adipose tissue

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, please tell your
doctor or pharmacist. You can also report side effects directly through the national reporting system detailed in
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Envarsus

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the box, blister and
packaging after ‘Scad.’ or ‘EXP’. The expiry date refers to the last day of that month.
Do not store at a temperature above 25 ºC.
Store in the original aluminium packaging to protect the medicine from light.
Use all prolonged-release tablets within 45 days of opening the aluminium packaging.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Envarsus contains

• The active substance 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 1.0 mg of tacrolimus (as monohydrate).
Envarsus 4 mg prolonged-release tablets
Each prolonged-release tablet contains 4.0 mg of tacrolimus (as monohydrate).

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

Description of Envarsus and package contents
Envarsus 0.75 mg prolonged-release tablets are oval, uncoated tablets, of colour from
white to off-white, with “0.75” imprinted on one side and “TCS” on the other side.
Envarsus 1 mg prolonged-release tablets are oval, uncoated tablets, of colour from
white to off-white, with “1” imprinted on one side and “TCS” on the other side.
Envarsus 4 mg prolonged-release tablets are oval, uncoated tablets, of colour from
white to off-white, with “4” imprinted on one side and “TCS” on the other side.
Envarsus is supplied in PVC/alu blister packs containing 10 tablets. 3 blisters are
packaged together inside a protective aluminium wrapper, which includes a desiccant.
Packs of 30, 60 and 90 prolonged-release tablets are available.
Not all pack sizes may be marketed.

Marketing authorisation holder
Chiesi Farmaceutici S.p.A.
Via Palermo, 26/A
43122 Parma
Italy

Manufacturer
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 Wien
Austria
For further information on this medicinal product, contact the local representative of the marketing
authorisation holder:

België/Belgique/Belgien
Chiesi sa/nv
Tél/Tel: +32 (0)2 788 42 00

Lietuva
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

България
Chiesi Bulgaria EOOD
Teл.: +359 29201205

Luxembourg/Luxemburg
Chiesi sa/nv
Tél/Tel: +32 (0)2 788 42 00

Česká republika
Chiesi CZ s.r.o.
Tel: +420 261221745

Magyarország
Chiesi Hungary Kft.
Tel.: +36-1-429 1060

Danmark
Chiesi Pharma AB
Tlf: +46 8 753 35 20

Malta
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791

Deutschland
Chiesi GmbH
Tel: +49 40 89724-0

Nederland
Chiesi Pharmaceuticals B.V.
Tel: +31 0 88 5016400

Eesti
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

Norge
Chiesi Pharma AB
Tlf: +46 8 753 35 20

Ελλάδα
Chiesi Hellas AEBE
Τηλ: +30 210 6179763

Österreich
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

España
Chiesi España, S.A.U.
Tel: +34 93 494 8000

Polska
Chiesi Poland Sp. z.o.o.
Tel.: +48 22 620 1421

France
Chiesi S.A.S
Tél: +33 1 47688899

Portugal
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791

Hrvatska
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

România
Chiesi Romania S.R.L.
Tel: +40 212023642

Ireland
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791

Slovenija
CHIESI SLOVENIJA, d.o.o.
Tel: +386-1-43 00 901

Ísland
Chiesi Pharma AB
Sími: +46 8 753 35 20

Slovenská republika
Chiesi Slovakia s.r.o.
Tel: +421 259300060

Italia
Chiesi Italia S.p.A.
Tel: +39 0521 2791

Suomi/Finland
Chiesi Pharma AB
Puh/Tel: +46 8 753 35 20

Κύπρος
Chiesi Farmaceutici S.p.A.
Τηλ: +39 0521 2791

Sverige
Chiesi Pharma AB
Tel: +46 8 753 35 20

Latvija
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

United Kingdom (Northern Ireland)
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791

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

ANNEX IV
SCIENTIFIC CONCLUSIONS AND JUSTIFICATION FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION
Scientific conclusions
In light of the assessment of the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSUR) for tacrolimus (systemic formulations), the PRAC’s scientific conclusions are as follows:
In light of the available data on cases of Kaposi’s sarcoma from clinical studies, the literature and spontaneous reports, including cases with a close temporal association and a number of fatal cases, and in light of a plausible mechanism of action, the PRAC considers that a causal relationship between systemic tacrolimus and Kaposi’s sarcoma is at least a reasonable possibility. The PRAC concluded that the product information for products containing systemic tacrolimus should be amended accordingly.
Having examined the PRAC’s recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and with the justification for the recommendation.

Justification for the variation of the terms of the marketing authorisation
Based on the scientific conclusions on tacrolimus (systemic formulations), the CHMP considers that
the benefit-risk ratio of the medicinal products containing tacrolimus (systemic formulations) remains
unchanged, save for the proposed changes to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation.