Rapamune (sirolimus) – Package leaflet - L04AA10

If you are considered to be at high risk for 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).

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 ethanol (alcohol)

Rapamune contains up to 2.5 vol % ethanol (alcohol). An initial dose of 6 mg contains up to 150 mg of alcohol which isequivalent to 3 mL beer or 1.25 mL wine. This amount of alcohol may be harmful for those suffering from alcoholism as well as for pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy. Alcohol may modify or increase the effect of other medicines.

Maintenance doses of 4 mg or less contain small amounts of ethanol (100 mg or less) that are likely to be too low to be harmful.

3.How to take Rapamune

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.

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.

Rapamune is for oral use only. Inform your doctor if you have difficulty taking the oral solution.

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

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 to stop you rejecting your transplanted organ. 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

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.

6. Contents of the pack and other information

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, mono-and diglycerides, ethanol, soya fatty acids, and ascorbyl palmitate).

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) containing 60 mL of Rapamune solution, one syringe adapter, 30 dosing syringes (amber plastic) and one syringe carry case.

Marketing Authorisation Holder and Manufacturer

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

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

If you are considered to be at high risk for 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).

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.

3.How to take Rapamune

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.

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.

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.

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.

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 to stop rejecting your transplanted organ. 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.

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 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.

6. Contents of the pack 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 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, Ammonium Hydroxide, 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

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

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