sirolimus: package leaflet

Hyftor contains the active substance sirolimus, which is a medicine that reduces the activity of the immune system.
In patients with tuberous sclerosis complex a protein that regulates the immune system, m-TOR, is overactive. By blocking the activity of m-TOR, Hyftor regulates cell growth and reduces the number or size of angiofibromas.

Hyftor is a medicine used to treat adults and children from 6 years of age with angiofibroma on the face resulting from tuberous sclerosis complex. Tuberous sclerosis complex is a rare genetic disease causing non-cancerous tumours to grow in different organs of the body, including the brain and skin.
The disease causes facial angiofibromas, non-cancerous lesions (growths) of the skin and mucous membranes (moist body surfaces, such as the lining of the mouth) in the face, in many patients.

Do not use Hyftor if you are allergic to sirolimus or any of the other ingredients of this medicine (listed in section 6)

Warnings and precautions
Talk to your doctor before using Hyftor if you have:
- a weakened immune system
- severely reduced liver function

Avoid contact of Hyftor with the eyes, the lining of the mouth and nose, or wounds. Similarly, it should not be used on irritated skin or skin that is infected or otherwise damaged.
In case of accidental contact it is recommended to immediately wash the gel off.

Avoid exposing skin treated with Hyftor to direct sunlight since it may cause side effects on the skin.
This includes both natural and artificial (for example in the solarium) sunlight. Your doctor will advise you about appropriate sun protection, like the use of sunscreen and clothing to cover the skin or wearing headgear.

Children
Hyftor is not recommended for children under 6 years since the product has not been sufficiently studied in this age group.

Other medicines and Hyftor
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Do not apply other medicines to the area of skin treated with Hyftor.

Pregnancy and breast-feeding
Hyftor is not recommended during pregnancy unless your doctor thinks that the benefits of treatment are greater than the risks. There is no information on the use of Hyftor in pregnant women.
Women of childbearing potential should use safe contraception during treatment with Hyftor.

It is not known, whether sirolimus is excreted into human milk after treatment with Hyftor. You and your doctor should made a decision whether to discontinue breast-feeding or to discontinue/abstain from Hyftor therapy taking into account the benefit of breast feeding for your child and the benefit of therapy for you.

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 using this medicine.

Driving and using machines
This medicine is not expected to affect the ability to drive or use machines.

Hyftor contains alcohol
This medicine contains 458 mg alcohol (ethanol) in each gram. It may cause a burning sensation when applied to damaged skin.

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is
Your doctor or pharmacist will show you how much gel you should use.

About 0.5 cm of the gel strand twice daily is recommended for a lesion of around 7 by 7 cm (50 cm2).

The maximum recommended dose on the face is:
- children 6 to 11 years: no more than 1 cm gel strand twice daily
- adults and children from 12 years: no more than 1.25 cm gel strand twice daily

How to apply the gel
Apply a thin layer of Hyftor twice daily (morning and evening) to the affected skin area and rub in gently. The application should be done once in the morning and once in the evening before going to bed. Limit the use to skin areas affected by angiofibroma. Do not cover the affected skin after application of Hyftor.

Wash your hands carefully before and immediately after using the gel to avoid any unintentional spread or ingestion.

Duration of use
Your doctor will tell you how long you should use Hyftor for.

If you use more Hyftor than you should
Hyftor is applied to the skin and absorption into the body is minimal. This makes overdose very unlikely.
If you apply too much gel to a lesion, carefully wipe off the excess gel with a paper towel and throw away the towel.

If you or anybody else accidentally swallows some gel, contact your doctor immediately.

If you forget to use Hyftor
If you forget to use the medicine in the morning, apply the gel as soon as you remember immediately before your meal in the evening of the same day. After your meal in the evening, only administer Hyftor at bedtime on that day. If you forget to use the medicine at bedtime, skip that dose. Do not apply more gel to make up for a missed dose.

If you stop using Hyftor
Your doctor will tell you how long you should use Hyftor and when you can stop treatment. Do not stop using it without consulting your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common (may affect more than 1 in 10 people)
- dry skin
- itching skin
- acne
- irritation at the application site, such as reddening, burning stinging, itching, swelling and/or numbness

Common (may affect up to 1 in 10 people)
- bleeding at application site
- abnormal sensation, including at the application site, such as numbness, prickling, tingling and itchiness
- application site swelling
- eczema characterised by changes that occur when skin becomes abnormally dry, red, itchy and cracked
- dermal cyst (a cyst containing solid tissue or structures such as hair)
- rash, itchy rash
- peeling of skin
- skin irritation
- reddening
- bleeding of the skin
- dermatitis (inflammation of the skin), including contact dermatitis (inflammation of the skin after contact with the medicine), acneiform dermatitis (inflammation of the skin with small acne-like bumps), seborrhoeic dermatitis (skin condition affecting the head with scaly and red skin), solar dermatitis (inflammation of the skin after exposure to sunlight)
- dry, hard and scaly skin
- hives
- nodules
- boils
- tinea versicolour (a fungal infection of the skin)
- inflammation of the lining of the mouth
- increased sensitivity to light
- reddening of the eyelid

• red eye
• eye irritation
• conjunctivitis (redness and discomfort in the eye)
• inflammation of hair follicles
• sensations like numbness, tingling and pins and needles
• nasal discomfort

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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 carton and on the tube after EXP.
The expiry date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C).
Store in the original tube in order to protect from light.
Keep away from fire.

Throw away the tube and any remaining gel 4 weeks after opening.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Hyftor contains
- The active substance is sirolimus. Each gram of gel contains 2 mg of sirolimus
- The other ingredients are carbomer, anhydrous ethanol, trolamine and purified water (see section 2 “Hyftor contains alcohol”).

What Hyftor looks like and contents of the pack
Hyftor is a transparent, colourless gel. It is supplied in an aluminium tube containing 10 g of gel.

Pack size: 1 tube

Marketing Authorisation Holder
Plusultra pharma GmbH
Fritz-Vomfelde-Str. 36
40547 Düsseldorf
Germany

Manufacturer
HWI pharma services GmbH
Straßburger Straße 77
77767 Appenweier
Germany

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.

syringe adapter (plastic stopper) tightly into the bottle until it is fully inserted. Do not attempt to remove the syringe adapter from the bottle once inserted.

of the adapter.

amount of Rapamune oral solution as prescribed by your doctor by gently pulling out the plunger of the dosing syringe until the level of the oral solution is even with the appropriate mark on the dosing syringe. If bubbles form in the oral solution in the dosing syringe during withdrawal, empty the Rapamune solution back into the bottle and repeat the withdrawal procedure. You may need to repeat step 3 more than once to deliver your dose. Ensure the syringe stays firmly inserted in the adapter throughout this step.

it is necessary to carry your medication with you, fill the dosing syringe to the appropriate mark and place a cap securely on it – the cap should snap into place. Then place the capped dosing syringe in the carrying case provided. Once in the syringe the medication may be kept at room temperature (not exceeding 25C) or refrigerated and should be used within 24 hours.

60 mL of water or orange juice. Stir well for one minute and drink immediately at once. Refill the glass with at least 120 mL of water or orange juice, stir well, and drink immediately. No other liquids, including grapefruit juice, should be used for dilution. The dosing syringe and cap are to be used once and then discarded.

When refrigerated the solution in the bottle may develop a slight haze. If this occurs, simply bring your Rapamune oral solution to room temperature and shake gently. The presence of this haze does not affect the quality of Rapamune.

If you take more Rapamune than you should

If you have taken more medicine than you were told contact a doctor or go to the nearest hospital emergency department straight away. Always take the labelled medicine bottle with you, even if it is empty.

If you forget to take Rapamune

If you forget to take Rapamune, take it as soon as you remember, but not within 4 hours of the next dose of ciclosporin. After that, continue to take your medicines as usual. Do not take a double dose to make up for a forgotten dose, and always take Rapamune and ciclosporin approximately 4 hours apart.
If you miss a dose of Rapamune completely, you should inform your doctor.

If you stop taking Rapamune

Do not stop taking Rapamune unless your doctor tells you to, as you risk losing your transplant.

If you have any further questions on 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 everybody gets them.

Allergic reactions

You should see your doctor immediately if you experience symptoms, such as swollen face, tongue and/or back of the mouth (pharynx) and/or difficulties in breathing (angioedema), or a skin condition whereby the skin can peel off (exfoliative dermatitis). These may be symptoms of a serious allergic reaction.

Kidney damage with low blood cell counts (thrombocytopaenic purpura/haemolytic uraemic syndrome)

When taken with medicines called calcineurin inhibitors (ciclosporin or tacrolimus), Rapamune may increase the risk of kidney damage with low blood platelets and low red blood cell counts, with or without rash (thrombocytopaenic purpura/haemolytic uraemic syndrome). If you experience symptoms, such as bruising or rash, changes in your urine, or changes in behaviour, or any others that are serious, unusual or prolonged, contact your doctor.

Infections

Rapamune reduces your body’s own defence mechanisms. Consequently your body will not be as good as normal at fighting infections. So if you are taking Rapamune, you may therefore catch more infections than usual, such as infections of the skin, mouth, stomach and intestines, lungs and urinary tract (see list below). You should contact your doctor if you experience symptoms that are serious, unusual, or prolonged.

Side effect frequencies

Very common: may affect more than 1 in 10 people

−
Fluid collection around the kidney
−
Swelling of the body including hands and feet
−
Pain
−
Fever
−
Headache
−
Increased blood pressure
−
Stomach pain, diarrhoea, constipation, nausea
−
Low red blood cells, low blood platelets
−
Increased fat in the blood (cholesterol and/or triglycerides), increased blood sugar, low blood potassium, low blood phosphorus, increased lactate dehydrogenase in the blood, increased creatinine in the blood − Joint pain − Acne − Urinary tract infection − Pneumonia and other bacterial, viral, and fungal infections − A reduced number of infection-fighting cells in the blood (white blood cells)

−
Diabetes
−
Abnormal tests of liver function, elevated AST and/or ALT liver enzymes
−
Rash
−
Elevated protein in the urine
−
Menstrual disorders (including absent, infrequent or heavy periods)
−
Slow healing (this may include separation of the layers of a surgical wound or stitch line) − Rapid heart rate − There is a general tendency for fluid to collect in various tissues.

Common: may affect up to 1 in 10 people

−
Infections (including life-threatening infections)
−
Blood clots in the legs
−
Blood clots in the lung
−
Mouth sores
−
Fluid collection in the abdomen
−
Kidney damage with low blood platelets and low red blood cell counts, with or without rash (haemolytic uraemic syndrome) − Low levels of a type of white blood cells called neutrophils − Deterioration of bone − Inflammation that may lead to lung damage, fluid around the lung − Nose bleeds − Skin cancer − Kidney infection − Ovarian cysts − Fluid collection in the sac around the heart, that in some cases may decrease the heart's ability to pump blood − Inflammation of the pancreas − Allergic reactions − Shingles − Cytomegalovirus infection

Uncommon: may affect up to 1 in 100 people

−
Cancer of the lymph tissue (lymphoma/post-transplant lympho-proliferative disorder), combined lowering of red blood cells, white blood cells and blood platelets − Bleeding from the lung − Protein in the urine, occasionally severe and associated with side effects, such as swelling − Scarring in the kidney that may reduce kidney function − Too much fluid collecting in the tissues due to irregular lymph function − Low blood platelets, with or without rash (thrombocytopaenic purpura) − Serious allergic reactions that can cause peeling of the skin − Tuberculosis − Epstein-Barr virus infection − Infectious diarrhoea with Clostridium difficile − Serious liver damage

Rare: may affect up to 1 in 1,000 people

−
Protein build-up in the air sacs of the lungs that may interfere with breathing
−
Serious allergic reactions that can affect blood vessels (see above paragraph on allergic reactions)

Not known: frequency cannot be estimated from the available data

−
Posterior reversible encephalopathy syndrome (PRES), a serious nervous system syndrome that has the following symptoms: headache, nausea, vomiting, confusion, seizures, and visual loss.
Should any of these occur together, please contact your physician.

S-LAM patients experienced similar side effects to those of kidney transplant patients, with the addition of weight loss, which may affect up to 1 in 10 people.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5.
How to store Rapamune

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 carton after “EXP”. The expiry date refers to the last day of that month.

Store in a refrigerator (2C - 8C).

Keep Rapamune oral solution in its original bottle in order to protect from light.

Once the bottle has been opened, the contents should be kept refrigerated and used within 30 days. If necessary, you may store the bottle at room temperature up to 25C for a short period of time, but no longer than 24 hours.

Once the dosing syringe has been filled with Rapamune oral solution, it should be kept at room temperature, but not above 25C, for maximum 24 hours.

Once the contents of the dosing syringe have been diluted with water or orange juice, the preparation should be drunk immediately.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Rapamune contains

The active substance is sirolimus. Each mL of Rapamune oral solution contains 1 mg of sirolimus.

The other ingredients are:

Polysorbate 80 (E433) and phosal 50 PG (phosphatidylcholine, propylene glycol [E1520], mono-and diglycerides, ethanol, soya fatty acids, and ascorbyl palmitate).

This medicine contains approximately 350 mg propylene glycol (E1520) in each mL.

What Rapamune looks like and contents of the pack

Rapamune oral solution is a pale yellow to yellow solution supplied in a 60 mL bottle.

Each pack contains: one bottle (amber glass) with child-resistant plastic cap, containing 60 mL of solution, one syringe adapter, 30 dosing syringes (amber plastic) and one syringe carry case.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

Manufacturer:
Pfizer Service Company BV
Hermeslaan 11
1932 Zaventem
Belgium

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
Luxembourg/Luxemburg
Pfizer NV/SA
Tél/Tel: +32 (0)2 554 62 11

Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000
България
Пфайзер Люксембург САРЛ, Клон
България
Teл: +359 2 970 4333

Magyarország
Pfizer Kft.
Tel: +36 1 488 3700

Česká Republika
Pfizer, spol. s r.o.
Tel: +420 283 004 111
Malta
Vivian Corporation Ltd.
Tel: +35621 344610

Danmark
Pfizer ApS
Tlf: +45 44 201 100

Nederland
Pfizer bv
Tel: +31 (0)800 63 34 636

Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Norge
Pfizer AS
Tlf: +47 67 52 61 00
Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 666 7500

Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
PFIZER ΕΛΛΑΣ A.E.
Τηλ.: +30 210 6785 800
Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00
España
Pfizer, S.L.
Télf:+34914909900
Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500

France
Pfizer
Tél +33 (0)1 58 07 34 40
România
Pfizer Romania S.R.L
Tel: +40 (0) 21 207 28 00
Hrvatska
Pfizer Croatia d.o.o.
Tel: + 385 1 3908 777

Slovenija
Pfizer Luxembourg SARL, Pfizer, podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana Tel: +386 (0)1 52 11 400

Ireland
Pfizer Healthcare Ireland Unlimited Company
Tel: +1800 633 363 (toll free)
Tel: +44 (0)1304 616161

Slovenská Republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: + 421 2 3355 5500
Ísland
Icepharma hf
Tel: +354 540 8000

Suomi/Finland
Pfizer Oy
Puh/Tel: +358 (0)9 430 040
Italia
Pfizer S.r.l.
Tel: +39 06 33 18 21

Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00

Kύπρος
PFIZER ΕΛΛΑΣ Α.Ε. (Cyprus Branch)
T: +357 22 817690

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel. +371 67035775

This leaflet was last revised in MM/YYYY

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

Rapamune contains the active substance sirolimus, which belongs to a group of medicines called immunosuppressants. It helps to control your body’s immune system after you have received a kidney transplant.

Rapamune is used in adults to prevent your body from rejecting transplanted kidneys and is normally used with other immunosuppressant medicines called corticosteroids and initially (the first 2 to 3 months) with ciclosporin.

Rapamune is also used for the treatment of patients with sporadic lymphangioleiomyomatosis (S-LAM) with moderate lung disease or declining lung function. S-LAM is a rare progressive lung disease that affects predominantly women of childbearing age. The most common symptom of S-LAM is shortness of breath.

Do not take Rapamune

− if you are allergic to sirolimus or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor or pharmacist before taking Rapamune

−
If you have any liver problems or have had a disease which may have affected your liver, please tell your doctor as this may affect the dose of Rapamune that you receive and may result in your having additional blood tests.

−
Rapamune, like other immunosuppressive medicines, may decrease your body’s ability to fight infection, and may increase the risk of developing cancer of the lymphoid tissues and skin.
−
If you have a body mass index (BMI) greater than 30 kg/m2, you may be at increased risk of abnormal wound healing.
−
If you are considered to be at high risk for kidney rejection, such as if you had a previous transplant that was lost to rejection.

Your doctor will perform tests to monitor the levels of Rapamune in your blood. Your doctor will also perform tests to monitor your kidney function, your blood fat (cholesterol and/or triglycerides) levels and possibly your liver function, during treatment with Rapamune.

Exposure to sunlight and UV light should be limited by covering your skin with clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer.

Children and adolescents

There is limited experience on the use of Rapamune in children and adolescents less than 18 years of age. The use of Rapamune is not recommended in this population.

Other medicines and Rapamune

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Some medicines can interfere with the action of Rapamune and, therefore, dose adjustment of Rapamune may be required. In particular, you should inform your doctor or pharmacist if you are taking any of the following:

− any other immunosuppressant medicines.
− antibiotics or antifungal medicines used to treat infection e.g. clarithromycin, erythromycin, telithromycin, troleandomycin, rifabutin, clotrimazole, fluconazole, itraconazole. It is not recommended that Rapamune be taken with rifampicin, ketoconazole or voriconazole.
− any high blood pressure medicines or medicines for heart problems including nicardipine, verapamil and diltiazem.
− anti-epileptic medicines including carbamazepine, phenobarbital, phenytoin.
− medicines used to treat ulcers or other gastrointestinal disorders such as cisapride, cimetidine, metoclopramide.
− bromocriptine (used in the treatment of Parkinson’s disease and various hormonal disorders), danazol (used in the treatment of gynaecological disorders), or protease inhibitors (e.g., for HIV and hepatitis C such as ritonavir, indinavir, boceprevir, and telaprevir).
−
St. John’s Wort (Hypericum perforatum).
− letermovir (an antiviral medicine to prevent getting ill from cytomegalovirus).
− cannabidiol (uses amongst others include treatment of seizures).

The use of live vaccines should be avoided with the use of Rapamune. Before vaccinations, please inform your doctor or pharmacist that you are receiving Rapamune.

The use of Rapamune may lead to increased levels of cholesterol and triglycerides (blood fats) in your blood that may require treatment. Medicines known as “statins” and “fibrates” used to treat elevated cholesterol and triglycerides have been associated with an increased risk of muscle breakdown (rhabdomyolysis). Please inform your doctor if you are taking medicines to lower your blood fats.

The combined use of Rapamune with angiotensin-converting enzyme (ACE) inhibitors (a type of medicine used to lower blood pressure) may result in allergic reactions. Please inform your doctor if you are taking any of these medicines.

Rapamune with food and drink

Rapamune should be taken consistently, either with or without food. If you prefer to take Rapamune with food, then you should always take it with food. If you prefer to take Rapamune without food, then you should always take it without food. Food can affect the amount of medicine that gets into your bloodstream, and taking your medicine in a consistent way means that the blood levels of Rapamune remain more stable.

Rapamune should not be taken with grapefruit juice.

Pregnancy, breast-feeding and fertility

Rapamune should not be used during pregnancy unless clearly necessary. You must use an effective method of contraception during treatment with Rapamune and for 12 weeks after treatment has stopped. 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.

It is not known whether Rapamune passes into breast milk. Patients taking Rapamune should discontinue breast-feeding.

Decreased sperm count has been associated with the use of Rapamune and usually returns to normal once treatment is stopped.

Driving and using machines

Although Rapamune treatment is not expected to affect your ability to drive, if you have any concerns please consult your doctor.

Rapamune contains lactose and sucrose

Rapamune contains 86.4 mg of lactose and up to 215.8 mg of sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Your doctor will decide exactly what dose of Rapamune you must take and how often to take it.
Follow your doctor’s instructions exactly, and never change the dose yourself.

Rapamune is for oral use only. Do not crush, chew, or split the tablets. Inform your doctor if you have difficulty taking the tablet.

Multiples of 0.5 mg tablets should not be used as a substitute for 1 mg and 2 mg tablets, as the different strengths are not directly interchangeable.

Rapamune should be taken consistently, either with or without food.

Kidney Transplant
Your doctor will give you an initial dose of 6 mg as soon as possible after the kidney transplant operation. Then you will need to take 2 mg of Rapamune each day, until otherwise directed by your doctor. Your dose will be adjusted depending on the level of Rapamune in your blood. Your doctor will need to perform blood tests to measure Rapamune concentrations.

If you are also taking ciclosporin, then you must take the two medicines approximately 4 hours apart.

It is recommended that Rapamune be used first in combination with ciclosporin and corticosteroids.
After 3 months, your doctor may discontinue either Rapamune or ciclosporin, as it is not recommended that these medicines be taken together beyond this period.

Sporadic Lymphangioleiomyomatosis (S-LAM)
Your doctor will give you 2 mg of Rapamune each day, until otherwise directed by your doctor. Your dose will be adjusted depending on the level of Rapamune in your blood. Your doctor will need to perform blood tests to measure Rapamune concentrations.

If you take more Rapamune than you should

If you have taken more medicine than you were told to, contact a doctor or go to the nearest hospital emergency department as soon as possible. Always take the labelled blister with you, even if it is empty.

If you forget to take Rapamune

If you forget to take Rapamune, take it as soon as you remember, but not within 4 hours of the next dose of ciclosporin. After that, continue to take your medicines as usual. Do not take a double dose to make up for a forgotten dose, and always take Rapamune and ciclosporin approximately 4 hours apart.
If you miss a dose of Rapamune completely, you should inform your doctor.

If you stop taking Rapamune

Do not stop taking Rapamune unless your doctor tells you to, as you risk losing your transplant.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions

You should see your doctor immediately if you experience symptoms, such as swollen face, tongue and/or back of the mouth (pharynx) and/or difficulties in breathing (angioedema), or a skin condition whereby the skin can peel off (exfoliative dermatitis). These may be symptoms of a serious allergic reaction.

Kidney damage with low blood cell counts (thrombocytopaenic purpura/haemolytic uraemic syndrome)

When taken with medicines called calcineurin inhibitors (ciclosporin or tacrolimus), Rapamune may increase the risk of kidney damage with low blood platelets and low red blood cell counts, with or without rash (thrombocytopaenic purpura/haemolytic uraemic syndrome). If you experience symptoms such as bruising or rash, changes in your urine, or changes in behaviour or any others that are serious, unusual or prolonged, contact your doctor.

Infections

Rapamune reduces your body’s own defence mechanisms. Consequently your body will not be as good as normal at fighting infections. So if you are taking Rapamune, you may therefore catch more infections than usual, such as infections of the skin, mouth, stomach and intestines, lungs and urinary

tract (see list below). You should contact your doctor if you experience symptoms that are serious, unusual, or prolonged.

Side effect frequencies

Very common: may affect more than 1 in 10 people

−
Fluid collection around the kidney
−
Swelling of the body including hands and feet
−
Pain
−
Fever
−
Headache
−
Increased blood pressure
−
Stomach pain, diarrhoea, constipation, nausea
−
Low red blood cells, low blood platelets
−
Increased fat in the blood (cholesterol and/or triglycerides), increased blood sugar, low blood potassium, low blood phosphorus, increased lactate dehydrogenase in the blood, increased creatinine in the blood − Joint pain − Acne − Urinary tract infection − Pneumonia and other bacterial, viral, and fungal infections − A reduced number of infection-fighting cells in the blood (white blood cells) − Diabetes − Abnormal tests of liver function, elevated AST and/or ALT liver enzymes − Rash − Elevated protein in the urine − Menstrual disorders (including absent, infrequent or heavy periods) − Slow healing (this may include separation of the layers of a surgical wound or stitch line) − Rapid heart rate − There is a general tendency for fluid to collect in various tissues.

Common: may affect up to 1 in 10 people

−
Infections (including life-threatening infections)
−
Blood clots in the legs
−
Blood clots in the lung
−
Mouth sores
−
Fluid collection in the abdomen
−
Kidney damage with low blood platelets and low red blood cell counts, with or without rash (haemolytic uraemic syndrome) − Low levels of a type of white blood cells called neutrophils − Deterioration of bone − Inflammation that may lead to lung damage, fluid around the lung − Nose bleeds − Skin cancer − Kidney infection − Ovarian cysts − Fluid collection in the sac around the heart, that in some cases may decrease the heart's ability to pump blood − Inflammation of the pancreas − Allergic reactions − Shingles − Cytomegalovirus infection

Uncommon: may affect up to 1 in 100 people

−
Cancer of the lymph tissue (lymphoma/post-transplant lympho-proliferative disorder), combined lowering of red blood cells, white blood cells and blood platelets − Bleeding from the lung − Protein in the urine, occasionally severe and associated with side effects, such as swelling − Scarring in the kidney that may reduce kidney function − Too much fluid collecting in the tissues due to irregular lymph function − Low blood platelets, with or without rash (thrombocytopaenic purpura) − Serious allergic reactions that can cause peeling of the skin − Tuberculosis − Epstein-Barr virus infection − Infectious diarrhoea with Clostridium difficile − Serious liver damage

Rare: may affect up to 1 in 1,000 people

−
Protein build-up in the air sacs of the lungs that may interfere with breathing
−
Serious allergic reactions that can affect blood vessels (see above paragraph on allergic reactions)

Not known: frequency cannot be estimated from the available data

−
Posterior reversible encephalopathy syndrome (PRES), a serious nervous system syndrome that has the following symptoms: headache, nausea, vomiting, confusion, seizures, and visual loss.
Should any of these occur together, please contact your physician.

S-LAM patients experienced similar side effects to those of kidney transplant patients, with the addition of weight loss, which may affect up to 1 in 10 people.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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 blister and carton after “EXP”.
The expiry date refers to the last day of that month.

Do not store above 25˚C.

Keep the blister in the outer carton in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Rapamune contains

The active substance is sirolimus.
Each Rapamune 0.5 mg coated tablet contains 0.5 mg of sirolimus.
Each Rapamune 1 mg coated tablet contains 1 mg of sirolimus.
Each Rapamune 2 mg coated tablet contains 2 mg of sirolimus.

The other ingredients are:

Tablet core: lactose monohydrate, macrogol, magnesium stearate, talc
Tablet coating: macrogol, glycerol monooleate, pharmaceutical glaze, calcium sulfate, microcrystalline cellulose, sucrose, titanium dioxide, poloxamer 188, -tocopherol, povidone, carnauba wax, Printing ink (Shellac, Iron Oxide Red, Propylene Glycol [E1520], Concentrated Ammonia Solution, Simethicone). The 0.5 mg and 2 mg tablets also contain yellow iron oxide (E172) and brown iron oxide (E172).

What Rapamune looks like and contents of the pack

Rapamune 0.5 mg is supplied to you as tan-coloured, triangular-shaped, coated tablets marked “RAPAMUNE 0.5 mg” on one side.

Rapamune 1 mg is supplied to you as white-coloured, triangular-shaped, coated tablets marked “RAPAMUNE 1 mg” on one side.

Rapamune 2 mg is supplied to you as yellow to beige-coloured, triangular-shaped, coated tablets marked “RAPAMUNE 2 mg” on one side.

The tablets are supplied in blister packs of 30 and 100 tablets. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

Manufacturer:
Pfizer Ireland Pharmaceuticals Unlimited Company
Little Connell
Newbridge
Co. Kildare
W12 HX57
Ireland

Pfizer Manufacturing Deutschland GmbH
Mooswaldallee 1
79108 Freiburg Im Breisgau
Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
Luxembourg/Luxemburg
Pfizer NV/SA
Tél/Tel: +32 (0)2 554 62 11
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000

България
Пфайзер Люксембург САРЛ, Клон
България
Teл: +359 2 970 4333

Magyarország
Pfizer Kft.
Tel: +36 1 488 3700

Česká Republika
Pfizer, spol. s r.o.
Tel: +420 283 004 111
Malta
Vivian Corporation Ltd.
Tel: +35621 344610

Danmark
Pfizer ApS
Tlf: +45 44 201 100

Nederland
Pfizer bvTel: +31 (0)800 63 34 636

Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Norge
Pfizer AS
Tlf: +47 67 52 61 00
Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 666 7500
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
PFIZER ΕΛΛΑΣ A.E.
Τηλ.: +30 210 6785 800
Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00
España
Pfizer, S.L.
Télf:+34914909900
Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500
France
Pfizer
Tél +33 (0)1 58 07 34 40
România
Pfizer Romania S.R.L
Tel: +40 (0) 21 207 28 00
Hrvatska
Pfizer Croatia d.o.o.
Tel: + 385 1 3908 777

Slovenija
Pfizer Luxembourg SARL, Pfizer, podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana Tel: +386 (0)1 52 11 400

Ireland
Pfizer Healthcare Ireland Unlimited Company
Tel: +1800 633 363 (toll free)
Tel: +44 (0)1304 616161

Slovenská Republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: + 421 2 3355 5500
Ísland
Icepharma hf
Tel: +354 540 8000

Suomi/Finland
Pfizer Oy
Puh/Tel: +358 (0)9 430 040
Italia
Pfizer S.r.l.
Tel: +39 06 33 18 21

Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00

Kύπρος
PFIZER ΕΛΛΑΣ Α.Ε. (Cyprus Branch)
T: +357 22 817690

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel. +371 67035775

This leaflet was last revised in MM/YYYY

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