Package leaflet: Information for the user

Rapamune 1 mg/ml oral solution

sirolimus
Please read all of 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 give it to other people, even if they have the same symptoms as yours, because it may be harmful.
If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Rapamune is and what it is used for
What you need to know before taking Rapamune
How to take Rapamune
Possible side effects
How to store Rapamune
Contents of the pack and other information

1. What Rapamune is and what it is used for

Rapamune contains the active substance sirolimus, which belongs to a group of medicines called immunosuppressants. It helps control the body's immune system after a kidney transplant.
Rapamune is used in adults to prevent the body from rejecting a transplanted kidney and is usually used in combination with other immunosuppressive medicines called corticosteroids and, initially (for the first 2–3 months), with ciclosporin.
Rapamune is also used to treat patients with sporadic lymphangioleiomyomatosis (S-LAM) who have moderate lung disease or declining lung function. S-LAM is a rare, progressive lung disease that primarily affects women of childbearing age. The most common symptom of LAM is shortness of breath.

2. What you need to know before taking Rapamune

Do not take Rapamune:

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

Warnings and precautions
Talk to your doctor or pharmacist before taking Rapamune

If you have liver problems or have had a disease that may have affected the liver, inform your doctor, as this may affect the dose of Rapamune you receive and additional blood tests may be required.
Rapamune, like other immunosuppressive medicines, may reduce your body’s ability to fight infections and may increase the risk of developing lymphatic tissue and skin tumors.
If your body mass index (BMI) is greater than 30 kg/m², there may be an increased risk of abnormal wound healing.
If you are considered at high risk of kidney transplant rejection, such as someone who has previously received another organ transplant followed by rejection.

Your doctor will perform tests to monitor Rapamune levels in your blood. Your doctor will also carry out tests to monitor kidney function, blood fat levels (cholesterol and/or triglycerides), and possibly liver function during treatment with Rapamune.
Exposure to sunlight and UV light should be limited by covering the skin with suitable clothing and using a high-protection sunscreen, as the risk of skin cancer is increased.
Children and adolescents
There is limited experience with the use of Rapamune in children and adolescents under 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 may interfere with the action of Rapamune, and therefore a dose adjustment of Rapamune may be necessary. In particular, inform your doctor or pharmacist if you are taking:

any other immunosuppressive medicine.
antibiotics or antifungal medicines used to treat infections, for example clarithromycin, erythromycin, telithromycin, troleandomycin, rifabutin, clotrimazole, fluconazole, itraconazole. The use of Rapamune with rifampicin, ketoconazole, or voriconazole is not recommended.
any antihypertensive medicines or medicines for heart problems, including nicardipine, verapamil, and diltiazem.
antiepileptic medicines including carbamazepine, phenobarbital, phenytoin.
medicines used to treat ulcers or other gastrointestinal disorders such as cisapride, cimetidine, metoclopramide.
bromocriptine (used to treat Parkinson’s disease and various hormonal imbalances), danazol (used to treat gynecological 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 used to prevent cytomegalovirus disease).
cannabidiol (uses include, among others, the treatment of seizures).

The use of live vaccines during treatment with Rapamune should be avoided. Before any vaccination, inform your doctor or pharmacist that you are taking Rapamune.
Taking Rapamune may cause an increase in blood cholesterol and triglyceride levels (fats in the blood), which may require treatment. Medicines known as "statins" and "fibrates," used to treat high cholesterol and triglycerides, have been associated with an increased risk of muscle breakdown (rhabdomyolysis). Inform your doctor if you are taking medicines to lower blood fat levels.
The use of Rapamune together with angiotensin-converting enzyme (ACE) inhibitors (a type of medicine used to lower blood pressure) may cause allergic reactions. Inform your doctor if you are taking any of these medicines.
Rapamune with food and drink
Rapamune should always be taken under the same conditions, either with food or on an empty stomach. If you prefer to take Rapamune with food, you must continue to take it with food. If you prefer to take Rapamune without food, you must continue to take it without food. Food can affect the amount of medicine in your blood; therefore, taking the medicine consistently under the same conditions will result in more stable blood levels of Rapamune.
Rapamune must not be taken with grapefruit juice.
Pregnancy, breastfeeding, and fertility
Rapamune must not be taken during pregnancy unless strictly necessary.
Effective contraceptive methods must be used during treatment with Rapamune and for 12 weeks after stopping treatment. If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
It is not known whether Rapamune is excreted in breast milk. Women taking Rapamune should discontinue breastfeeding.
A decrease in sperm count has been associated with the use of Rapamune and generally returns to normal after stopping treatment.
Driving and using machines
Although it is not expected that treatment with Rapamune will affect your ability to drive, if you have any doubts, consult your doctor.
Rapamune contains ethanol (alcohol)
Rapamune contains up to 3.17% by volume of ethanol (alcohol). An initial dose of 6 mg contains up to 150 mg of alcohol, equivalent to 3.80 ml of beer or 1.58 ml of wine. This amount of alcohol may be harmful to individuals with alcoholism, pregnant or breastfeeding women, children, and high-risk groups such as patients with epilepsy or liver disease. Alcohol may alter or increase the effect of other medicines.
Maintenance doses of 4 mg or lower contain small amounts of ethanol (100 mg or less) which are likely too low to be harmful.

3. How to take Rapamune

Take this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist.
Your doctor will determine the exact dose of Rapamune you should take and how often.
Follow your doctor's instructions precisely and never change the dose on your own initiative.
Rapamune is for oral use only. Inform your doctor if you have difficulty taking the oral solution.
Rapamune should always be taken under the same conditions, either with or without food.

Kidney transplant
Generally, for an adult, your doctor will prescribe an initial dose of 6 mg as soon as possible after kidney transplantation. Afterwards, you will need to take 2 mg of Rapamune daily, unless your doctor decides otherwise. Your dose will be adjusted based on the concentration of Rapamune in your blood. Your doctor will need to perform blood tests to monitor Rapamune levels.

If you are also taking cyclosporine, you must take the two medicines approximately 4 hours apart.
Rapamune is initially recommended to be taken in combination with cyclosporine and corticosteroids. After 3 months, your doctor may discontinue either Rapamune or cyclosporine, as it is not recommended to take both medicines together for longer periods.

Spontaneous lymphangioleiomyomatosis (S-LAM)
Your doctor will prescribe 2 mg of Rapamune daily, unless otherwise indicated. The dose will be adjusted according to the level of Rapamune in your blood. Your doctor will perform blood tests to measure Rapamune concentrations.

Instructions for diluting Rapamune

Remove the safety cap from the vial by pressing the tabs on the cap and unscrewing it. Insert the syringe adapter into the vial until it is level with the top edge of the vial. Do not attempt to remove the syringe adapter from the vial once inserted.

A hand holds a small glass vial while a needle inserted into the stopper draws liquid from it

With the plunger fully depressed, insert one of the dosing syringes into the opening of the syringe adapter.

Two illustrations show a hand pressing the plunger of a syringe downward to draw liquid from a glass vial

Draw up the exact amount of Rapamune oral solution as prescribed by your doctor, gently pulling back the plunger of the dosing syringe until the level of the oral solution aligns with the appropriate mark on the dosing syringe. Keep the vial in an upright position during this process. If air bubbles form in the oral solution within the dosing syringe, empty the Rapamune solution back into the vial and repeat the drawing-up procedure. You may need to repeat step 3 more than once before administering the dose.

A hand holds a syringe to aspirate liquid from a glass vial, with a magnified view showing the level of the contents

You may have been instructed to take the Rapamune oral solution at a specific time of day. If you need to carry the medicine with you, fill the dosing syringe to the appropriate mark and close it securely with a cap – the cap should click into place. Then place the closed dosing syringe into the provided transport container. Once drawn into the syringe, the medicine can be kept at room temperature (not above 25°C) or refrigerated and must be used within 24 hours.

A hand holds a syringe horizontally above an open rectangular container preparing the medication

Technical drawing showing two hands preparing a syringe and pouring its contents into a glass

Pour the contents of the dosing syringe into a container made only of glass or plastic, containing at least 60 ml of water or orange juice. Mix well for one minute and drink immediately. Refill the glass with at least 120 ml of water or orange juice, mix well, and drink immediately. No other liquid, including grapefruit juice, should be used for dilution. The dosing syringe and cap should be used only once and then discarded.

When refrigerated, the solution in the vial may develop a slight cloudiness. If this occurs, simply allow the Rapamune oral solution to reach room temperature and gently agitate it. This cloudiness does not affect the quality of Rapamune.

If you take more Rapamune than you should
If you have taken more medicine than prescribed, contact a doctor or go immediately to the nearest hospital emergency department. Always carry the labeled medicine vial with you, even if 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 your next cyclosporine dose. Then continue taking the medicine as usual. Do not take a double dose to make up for the missed dose, and always take Rapamune and cyclosporine approximately 4 hours apart. If you completely miss a dose of Rapamune, you must inform your doctor.

If you stop taking Rapamune
Do not stop taking Rapamune unless instructed by your doctor, as you risk losing the transplanted organ.

If you have any questions about the use of this medicine, consult 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 must contact your doctor immediately if you experience symptoms such as swelling of the face, tongue and/or pharynx (back of the mouth) and/or difficulty breathing (angioedema), or a skin condition which may cause your skin to peel off (exfoliative dermatitis). These may be symptoms of a severe allergic reaction.

Kidney damage associated with anaemia (thrombocytopenic purpura/haemolytic-uraemic syndrome)
When taken with medicines called calcineurin inhibitors (cyclosporine or tacrolimus), Rapamune may increase the risk of kidney damage with thrombocytopenia and anaemia, with or without rash (thrombocytopenic purpura/haemolytic-uraemic syndrome). If you experience symptoms such as bruising or rash, changes in your urine, or changes in behaviour or other severe, unusual or prolonged symptoms, contact your doctor.

Infections
Rapamune reduces your body's defence mechanisms. As a result, your body may not be able to fight infections as effectively as normal. Therefore, if you are taking Rapamune, you may get more infections than usual, such as infections of the skin, mouth, stomach and intestine, lungs and urinary tract (see list below). If your symptoms are severe, unusual or prolonged, you must contact your doctor.

Frequency of side effects

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

Fluid accumulation around the kidney
Swelling of the body, including hands and feet
Pain
Fever
Headache
Increased blood pressure
Abdominal pain, diarrhoea, constipation, nausea
Anaemia, thrombocytopenia
Increased blood fats (cholesterol and/or triglycerides), increased blood sugar, low blood potassium levels, low blood phosphate levels, increased blood lactate dehydrogenase protein, elevated blood creatinine levels
Joint pain
Acne
Urinary tract infections
Pneumonia and other bacterial, viral and fungal infections
Decreased number of blood cells that fight infections (white blood cells)
Diabetes
Abnormal liver function tests, increased liver enzymes AST and/or ALT
Rash (skin eruption)
Increased protein in the urine
Menstrual disorders (including amenorrhoea, dysmenorrhoea or heavy menstruation)
Delayed wound healing (which may include separation of surgical wound edges or suture lines)
Tachycardia
General tendency for fluid accumulation in various tissues

Common (may affect up to 1 in 10 people)

Infections (including life-threatening infections)
Blood clots in the vessels of the legs
Blood clots in the lung
Mouth ulcers
Fluid accumulation in the abdomen
Kidney damage with thrombocytopenia and anaemia, with or without rash (haemolytic-uraemic syndrome)
Decreased number of neutrophils (a type of white blood cell)
Bone deterioration
Inflammation that may lead to lung damage, fluid around the lungs
Nosebleeds
Skin tumour
Kidney infection
Ovarian cysts
Fluid accumulation in the sac around the heart, which in some cases may reduce the heart's ability to pump blood
Pancreatitis
Allergic reactions
Herpes zoster (shingles)
Cytomegalovirus infection

Uncommon (may affect up to 1 in 100 people)

Cancer of the lymphatic tissue (lymphoma/post-transplant lymphoproliferative disorders), simultaneous decrease in red blood cells, white blood cells and platelets
Bleeding from the lungs
Protein in the urine, occasionally severe and associated with side effects such as swelling
Scarring of the kidney which may reduce kidney function
Fluid accumulation in tissues due to impaired lymphatic system function
Thrombocytopenia, with or without rash (thrombocytopenic purpura)
Severe allergic reactions which may cause skin peeling
Tuberculosis
Epstein-Barr virus infection
Infectious diarrhoea due to Clostridium difficile
Severe liver damage

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

Accumulation of protein in the lung alveoli, which may interfere with breathing
Severe allergic reactions which may affect blood vessels (see the section on allergic reactions above)

Not known (frequency cannot be estimated from the available data)

Posterior reversible encephalopathy syndrome (PRES), a serious nervous system disorder with the following symptoms: headache, nausea, vomiting, confusion, seizures, and loss of vision. If these symptoms occur together, please contact your doctor.

Patients with S-LAM have experienced side effects similar to those in kidney transplant patients, with the additional occurrence of weight loss, which may affect more than 1 in 10 people.

Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex 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 stated on the cardboard carton after "EXP". The expiry date refers to the last day of the month.
Store in the refrigerator (2°C - 8°C).
Keep Rapamune oral solution in its original vial to protect the medicine from light.
Once the vial has been opened, the contents must be stored in the refrigerator and used within 30 days.
If necessary, the vial may be stored at room temperature up to 25°C for a short period of time, but not for more than 24 hours.
Once filled with Rapamune oral solution, the oral dosing syringe must be stored at room temperature, but not above 25°C, for a maximum of 24 hours.
After diluting the contents of the dosing syringe with water or orange juice, the resulting preparation should be taken immediately.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Rapamune contains
The active substance is sirolimus. Each ml of Rapamune oral solution contains 1 mg of sirolimus.
The excipients are:
Polysorbate 80 (E433) and Phosal 50 PG (phosphatidylcholine, propylene glycol [E1520], mono- and diglycerides, ethanol, soybean fatty acids and ascorbyl palmitate).
Each ml of this medicinal product contains approximately 350 mg of propylene glycol (E1520).

Description of the appearance of Rapamune 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) containing 60 ml of Rapamune solution, a syringe adapter, 30 amber polypropylene dosing syringes, and a syringe holder.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Brussels
Belgium

Manufacturer:
Pfizer Service Company BV
Hoge Wei 10
1930 Zaventem
Belgium

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

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

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

Česká Republika
Pfizer, spol. s r.o.
Tel: +420 283 004 111

Danmark
Pfizer ApS
Tlf: +45 44 201 100

Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000

Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 666 7500

Ελλάδα
PFIZER ΕΛΛΑΣ A.E.
Τηλ.: +30 210 6785 800

España
Pfizer, S.L.
Télf: +34 914909900

France
Pfizer
Tél: +33 (0)1 58 07 34 40

Hrvatska
Pfizer Croatia d.o.o.
Tel: +385 1 3908 777

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

Ísland
Icepharma hf
Tel: +354 540 8000

Italia
Pfizer S.r.l.
Tel: +39 06 33 18 21

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

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel: +371 67035775

Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel: +3705 2514000

Luxembourg/Luxemburg
Pfizer Luxembourg SARL
Tel: +32 (0)2 554 62 11

Magyarország
Pfizer Kft.
Tel: +36 1 488 3700

Malta
Vivian Corporation Ltd.
Tel: +356 21 344610

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

Norge
Pfizer AS
Tlf: +47 67 52 61 00

Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0

Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00

Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500

România
Pfizer Romania S.R.L
Tel: +40 (0) 21 207 28 00

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

Slovenská Republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421 2 3355 5500

Suomi/Finland
Pfizer Oy
Puh/Tel: +358 (0)9 430 040

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

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

Package leaflet: Information for the user

Rapamune 0.5 mg coated tablets, 1 mg coated tablets, 2 mg coated tablets

sirolimus
Please 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 give it to others, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

What Rapamune is and what it is used for
What you need to know before taking Rapamune
How to take Rapamune
Possible side effects
How to store Rapamune
Contents of the pack and other information

1. What Rapamune is and what it is used for

Rapamune contains the active substance sirolimus, which belongs to a group of medicines called immunosuppressants. It helps control your body's immune system after a kidney transplant.
Rapamune is used in adults to help prevent your body from rejecting the transplanted kidney and is usually used in combination with other immunosuppressive medicines called corticosteroids and initially (for the first 2–3 months) with cyclosporine.
Rapamune is also used to treat patients with sporadic lymphangioleiomyomatosis (S-LAM) who have moderate lung disease or declining lung function. LAM is a rare, progressive lung disease that primarily affects women of reproductive age. The most common symptom of LAM is shortness of breath.

2. What you need to know before taking Rapamune

Do not take Rapamune

if you are allergic to sirolimus or to 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 liver problems or have had a disease that may have affected your liver, inform your doctor, as this may affect the dose of Rapamune you receive and additional blood tests may be required.
Rapamune, like other immunosuppressive medicines, may reduce your body's ability to fight infections and may increase the risk of developing lymphatic tissue and skin tumors.
If your body mass index (BMI) is greater than 30 kg/m², there may be an increased risk of abnormal wound healing.
If you are considered to be at high risk of kidney transplant rejection, for example, if you have previously received another organ transplant that was subsequently lost due to rejection.

Your doctor will perform tests to monitor the levels of Rapamune in your blood. Your doctor will also carry out tests to monitor your kidney function, blood fat levels (cholesterol and/or triglycerides), and possibly your liver function during treatment with Rapamune.
Exposure to sunlight and UV light should be minimized by covering your skin with appropriate clothing and using a high-protection sunscreen, as the risk of skin cancer is increased.
Children and adolescents
Experience with the use of Rapamune in children and adolescents under 18 years of age is limited.
The use of Rapamune is not recommended in this population.
Other medicines and Rapamune
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Some medicines may interfere with the action of Rapamune, and therefore a dose adjustment of Rapamune may be necessary. In particular, inform your doctor or pharmacist if you are taking any of the following:

any other immunosuppressive medicine.
antibiotics or antifungal medicines used to treat infections, such as clarithromycin, erythromycin, telithromycin, troleandomycin, rifabutin, clotrimazole, fluconazole, itraconazole, ketoconazole, or voriconazole. The concomitant use of Rapamune with rifampicin, ketoconazole, or voriconazole is not recommended.
any antihypertensive medicines or medicines for heart conditions, including nicardipine, verapamil, and diltiazem.
antiepileptic 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 imbalances), danazol (used in the treatment of gynecological 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 used to prevent cytomegalovirus disease).
cannabidiol (uses include, among others, the treatment of seizures).

The use of live vaccines during treatment with Rapamune should be avoided. Before any vaccination, inform your doctor or pharmacist that you are taking Rapamune.
Treatment with Rapamune may cause increased blood levels of cholesterol and triglycerides (fats in the blood), which may require treatment. Medicines known as “statins” and “fibrates,” used to treat high cholesterol and triglycerides, have been associated with an increased risk of muscle breakdown (rhabdomyolysis). Inform your doctor if you are taking medicines to lower blood fat levels.
The use of Rapamune together with angiotensin-converting enzyme (ACE) inhibitors (a type of medicine used to lower blood pressure) may cause allergic reactions. Inform your doctor if you are taking any of these medicines.
Rapamune with food and drinks
Rapamune should always be taken under the same conditions—either with food or on an empty stomach. If you prefer to take Rapamune with food, you must continue to take it with food consistently. If you prefer to take Rapamune without food, you must continue to take it without food consistently. Food can affect the amount of medicine in your blood; therefore, taking the medicine consistently under the same conditions will result in more stable blood levels of Rapamune.
Rapamune must not be taken with grapefruit juice.
Pregnancy, breastfeeding, and fertility
Rapamune must not be taken during pregnancy unless strictly necessary.
Effective contraceptive methods must be used during treatment with Rapamune and for 12 weeks after stopping treatment. If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
It is not known whether Rapamune is excreted in human breast milk. Women taking Rapamune should discontinue breastfeeding.
A decrease in sperm count has been associated with the use of Rapamune and generally returns to normal after discontinuation of treatment.
Driving and using machines
Although treatment with Rapamune is not expected to affect your ability to drive, if you have any doubts, consult your doctor.
Rapamune contains lactose and sucrose
Rapamune contains 86.4 mg of lactose and up to 215.8 mg of sucrose. If your doctor has informed you that you have an intolerance to certain sugars, contact your doctor before taking this medicine.

3. How to take Rapamune

Always take this medicine exactly as your doctor has told you. If you have any doubts, consult your doctor or pharmacist.
Your doctor will decide the exact dose of Rapamune you should take and how often.
Follow your doctor's instructions precisely and never change the dose on your own initiative.
Rapamune is for oral use only. Do not crush, chew or split the tablets. Inform your doctor if you have difficulty swallowing the tablet.
Multiples of the 0.5 mg tablets must not be used as substitutes for the other tablet strengths of 1 mg and 2 mg, as the different strengths are not directly interchangeable.
Rapamune should always be taken under the same conditions, either with or without food.

Kidney transplant
Your doctor will prescribe an initial dose of 6 mg as soon as possible after kidney transplantation surgery.
Afterwards, you will need to take 2 mg of Rapamune daily, unless your doctor decides otherwise. Your dose will be adjusted according to the concentration of Rapamune in your blood. Your doctor will need to perform blood tests to determine Rapamune levels.
If you are also taking cyclosporine, you must take the two medicines approximately 4 hours apart.
Rapamune is initially recommended to be taken in combination with cyclosporine and corticosteroids. After 3 months, your doctor may discontinue either Rapamune or cyclosporine, as it is not recommended to take both medicines together for longer periods.

Spontaneous lymphangioleiomyomatosis (S-LAM)
Your doctor will prescribe 2 mg of Rapamune daily, until otherwise indicated. The dose will be adjusted based on the level of Rapamune in your blood. Your doctor will perform blood tests to monitor Rapamune concentrations.

If you take more Rapamune than you should
If you have taken more medicine than you were told to take, consult a doctor or go immediately to the nearest hospital emergency department. Always bring the labelled blister pack with you, even if it is empty.

If you forget to take Rapamune
If you forget to take a dose of Rapamune, take it as soon as you remember, but not within 4 hours of your next cyclosporine dose. Then continue taking the medicine as usual. Do not take a double dose to make up for a missed dose, and always take Rapamune and cyclosporine approximately 4 hours apart. If you completely miss a dose of Rapamune, you must inform your doctor.

If you stop taking Rapamune
Do not stop taking Rapamune unless your doctor tells you to do so, as you risk losing your transplanted organ.
If you have any further questions about this medicine, consult 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 must contact your doctor immediately if you experience symptoms such as swelling of the face, tongue and/or throat (back of the mouth) and/or difficulty breathing (angioedema), or a skin condition causing the skin to peel (exfoliative dermatitis). These may be symptoms of a serious allergic reaction.

Kidney damage associated with anaemia (thrombocytopenic purpura/haemolytic uraemic syndrome)
When taken with medicines called calcineurin inhibitors (cyclosporine or tacrolimus), Rapamune may increase the risk of kidney damage with thrombocytopenia and anaemia, with or without rash (thrombocytopenic purpura/haemolytic uraemic syndrome). If you experience symptoms such as bruising or rash, changes in urine, changes in behaviour, or other serious, unusual or prolonged symptoms, contact your doctor.

Infections
Rapamune reduces your body's natural defences. As a result, your body may not be as effective as usual in fighting infections. Therefore, if you are taking Rapamune, you may get more infections than usual, such as infections of the skin, mouth, stomach and intestine, lungs, and urinary tract (see list below). If your symptoms are severe, unusual or prolonged, you should contact your doctor.

Frequency of side effects

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

Fluid accumulation around the kidney
Swelling of the body, including hands and feet
Pain
Fever
Headache
Increased blood pressure
Abdominal pain, diarrhoea, constipation, nausea
Anaemia, thrombocytopenia
Increased levels of blood fats (cholesterol and/or triglycerides), increased blood sugar, low blood potassium levels, low blood phosphorus levels, increased blood lactate dehydrogenase protein, elevated blood creatinine levels
Joint pain
Acne
Urinary tract infections
Pneumonia and other bacterial, viral and fungal infections
Decreased number of blood cells that fight infections (white blood cells)
Diabetes
Abnormal liver function tests, increased liver enzymes AST and/or ALT
Rash (skin eruption)
Increased protein in the urine
Menstrual disorders (including amenorrhoea, dysmenorrhoea or heavy menstruation)
Delayed wound healing (which may include separation of surgical wound edges or suture lines)
Tachycardia
General tendency for fluid accumulation in various tissues

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

Infections (including life-threatening infections)
Blood clots in the blood vessels of the legs
Blood clots in the lung
Mouth ulcers
Fluid accumulation in the abdomen
Kidney damage with thrombocytopenia and anaemia, with or without rash (haemolytic uraemic syndrome)
Decreased number of neutrophils (a type of white blood cell)
Bone deterioration
Inflammation that may lead to lung damage, fluid around the lungs
Nosebleeds
Skin tumours
Kidney infection
Ovarian cysts
Fluid accumulation in the sac around the heart, which in some cases may reduce the heart's ability to pump blood
Pancreatitis
Allergic reactions
Shingles (herpes zoster)
Cytomegalovirus infection

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

Cancer of the lymphatic tissue (lymphoma/post-transplant lymphoproliferative disorders), simultaneous decrease in red blood cells, white blood cells and platelets
Bleeding from the lungs
Protein in the urine, occasionally severe and associated with side effects such as swelling
Scarring of the kidney which may reduce kidney function
Accumulation of excess fluid in tissues due to impaired lymphatic function
Thrombocytopenia, with or without rash (thrombocytopenic purpura)
Severe allergic reactions that may cause skin peeling
Tuberculosis
Epstein-Barr virus infection
Infectious diarrhoea caused by Clostridium difficile
Severe liver damage

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

Accumulation of protein in the lung alveoli, which may interfere with breathing
Severe allergic reactions that may affect blood vessels (see the section on allergic reactions above)

Not known: (frequency cannot be estimated from the available data)

Posterior reversible encephalopathy syndrome (PRES), a serious nervous system disorder with symptoms including headache, nausea, vomiting, confusion, seizures, and loss of vision. If these symptoms occur together, please contact your doctor immediately.

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

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex 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 blister and the cardboard carton after EXP. The expiry date refers to the last day of the month.
Do not store above 25°C.
Keep the blister in the outer packaging to protect the medicine from light.
Do not dispose of any medicine via 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 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 excipients are:
Tablet core: monohydrate lactose, macrogol, magnesium stearate, talc
Tablet coating: macrogol, glyceryl monooleate, pharmaceutical glaze, calcium sulfate, microcrystalline cellulose, sucrose, titanium dioxide, poloxamer 188, α-tocopherol, povidone, carnauba wax.
Printing ink (shellac, red iron oxide, 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).

Description of the Appearance of Rapamune and Contents of the Package
Rapamune 0.5 mg is supplied as light brown, triangular, coated tablets, marked on one side with "RAPAMUNE 0.5 mg".
Rapamune 1 mg is supplied as white, triangular, coated tablets, marked on one side with "RAPAMUNE 1 mg".
Rapamune 2 mg is supplied as yellowish-beige, triangular, coated tablets, marked on one side with "RAPAMUNE 2 mg".

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

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder:
Pfizer Ireland Pharmaceuticals
Little Connell, Newbridge, Co. Kildare
Ireland

Manufacturer:
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Brussels
Belgium

Pfizer Manufacturing Deutschland GmbH
Mooswaldallee 1
79108 Freiburg im Breisgau
Germany

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder.

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

България
Pfizer Luxembourg SARL, Klona Balgariya
Tel: +359 2 970 4333

Česká Republika
Pfizer, spol. s r.o.
Tel: +420 283 004 111

Danmark
Pfizer ApS
Tlf: +45 44 201 100

Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000

Eesti
Pfizer Luxembourg SARL, Eesti filiaal
Tel: +372 666 7500

Ελλάδα
PFIZER ELLAS A.E.
Tel: +30 210 6785 800

España
Pfizer, S.L.
Tel: +34 914909900