TORISEL 30 mg concentrate and diluent for solution forinfusion

Your doctor has prescribed TORISEL because you have one of the following types of cancer:

• Advanced cancer of the kidney (renal cancer).
• Previously treated mantle cell lymphoma, a type of cancer affecting the lymph nodes

TORISEL is a selective inhibitor of mTOR (mammalian target of rapamycin) that blocks tumour cell growth and division.

Do not use TORISEL

• If you are allergic (hypersensitive) to temsirolimus, to polysorbate 80 or any of the other ingredients of TORISEL
• If you are allergic (hypersensitive) to sirolimus (used to prevent the body from rejecting transplanted kidneys) since sirolimus is released from temsirolimus in the body.
• If you have mantle cell lymphoma and liver problems please tell your doctor.

Take special care with TORISEL

• If you are allergic (hypersensitive) to antihistamines or cannot take antihistamines for other medical reasons.
• If you have high cholesterol, TORISEL may elevate triglycerides and/or cholesterol. This may require treatment with lipid-lowering agents (medicine used to reduce cholesterol in the blood).
• If you are going to have an operation, if you have had recent major surgery, or if you still have an unhealed wound following surgery, you should tell your doctor before receiving this medicine, as TORISEL may increase the risk of problems with wound healing.
• If you are planning to have a vaccination during treatment with TORISEL, the vaccination may be less effective. The use of certain vaccinations should be avoided during treatment with TORISEL.
• If you have a history of kidney failure or kidney problems.
• If you have a history of liver problems.
• If you are a child or adolescent under 18 years of age, your doctor will consider the potential benefit to you in relation to any risk.
• If you are over 65 years of age, you may be more likely to have certain side effects, including swelling of your face, diarrhoea, pneumonia, anxiety, depression, shortness of breath, decreased number of white cells in the blood, muscle pain, change in the sense of taste, upper respiratory infection, fluid around the lungs, sores and inflammation in the mouth and/or the digestive tract and runny nose, dizziness and infections.
• If you have tumours in your brain or spinal cord, or are taking medicines to prevent your blood from clotting (such as warfarin), you may be more likely to have bleeding into your brain.

TORISEL may also

• increase blood glucose levels and worsen diabetes mellitus. This may result in the need for insulin and/or oral antidiabetic agent therapy. Tell your doctor if you experience any excessive thirst or increased frequency and quantity of urination.
• weaken your immune system; therefore, you may be at risk of getting an infection while you are taking TORISEL.
• cause shortness of breath, cough, and fever. Tell your doctor if you experience new or worsening symptoms.
• increase the risk of cerebral haemorrhage (bleeding in the brain).
• cause cataracts when taken with interferon-? (a medicine used in the treatment of hepatitis and cancer).
• cause serious allergic reactions. Tell your doctor if you experience difficulty in breathing and/or swelling of the face.
• cause a decrease in the number of cells that help blood to clot, which may increase the risk of bleeding.

Using TORISEL with other medicines

Some medicines can interfere with the breakdown or metabolism of TORISEL. In particular, you should inform your doctor if you are taking any of the following:

• protease inhibitors used in the treatment of HIV
• antibiotics (including rifampicin) or antifungal medicines (including ketoconazole) used to treat infections
• nefazodone or selective serotonin re-uptake inhibitors used to treat depression
• anti-epileptic medicines, including carbamazepine, phenytoin and phenobarbital
• rifabutin used to treat infection in people with HIV and other diseases
• herbal medicines or natural remedies containing St. John?s Wort ( Hypericum perforatum) used to treat mild depression
• Angiotensin converting enzyme (ACE) inhibitors used to treat high blood pressure or other cardiovascular problems (such as enalapril, ramipril, lisinopril), amphiphilic medicines used to treat heart arrhythmias (such as amiodarone), or statins used to treat high cholesterol

Using TORISEL with food and drink

• Grapefruit juice may increase blood concentrations of TORISEL and should be avoided.

Please tell your doctor if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

TORISEL has not been studied in pregnant women, and it must not be used during pregnancy. It is important that you tell your doctor if you are pregnant or are planning to become pregnant before receiving TORISEL.

Women of childbearing potential must avoid pregnancy by using an effective method of birth control during treatment with TORISEL. Men with partners of childbearing potential should use medically acceptable contraception while receiving TORISEL.

Women should not breast-feed during treatment with TORISEL, as this medicine may interfere with the growth and development of the baby. Ask your doctor for advice before breast-feeding your baby, as it is not known if TORISEL passes into breast milk.

Driving and using machines

No studies on the ability to drive and use machines have been performed. However, the very common side effects include feeling or being sick (nausea and vomiting) and difficulty falling or staying asleep. It is recommended you do not drive immediately after treatment.
For patients receiving the higher dose of TORISEL for the treatment of mantle cell lymphoma, the amount of alcohol in this medicinal product may impair your ability to drive or use machines.

Important information about some of the ingredients of TORISEL

This medicine contains ethanol (alcohol), equivalent to 17.6 ml beer, 7.3 ml wine per 25 mg dose. Patients receiving the higher dose of 175 mg of TORISEL for the initial treatment of mantle cell lymphoma may receive a dose of ethanol equivalent to up to 123 ml beer or 51 ml wine per dose. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines.

Children and adolescents

Insufficient data are available in patients under the age of 18 years. The treatment with this medicine is not recommended in children and adolescents.

TORISEL will always be prepared and given to you by a doctor or another healthcare professional as an intravenous infusion (into your vein).

TORISEL 30 mg concentrate must first be diluted with 1.8 ml of withdrawn diluent to achieve a concentration of 10 mg/ml before administration in sodium chloride 9 mg/ml (0.9%) solution for injection(see dilution instructions at the end of the package leaflet).

For renal cancer, the recommended dose is 25 mg infused (as a drip) over a 30- to 60-minute period once weekly.

For mantle cell lymphoma, the recommended dosing is 175 mg infused (as a drip) over a 30- to 60-minute period once weekly for 3 weeks followed by single weekly doses of 75 mg infused (as a drip) over a 30- to 60-minute period.

You should receive an injection of antihistamine (to try to prevent allergic reaction to TORISEL) directly into your vein approximately 30 minutes before your dose of TORISEL.

Treatment with TORISEL should continue until you are no longer benefiting from therapy or until unacceptable side effects occur.

If too much TORISEL is given or you miss a dose

As this medicine is prepared and given by a healthcare professional, it is unlikely you will be given too much.

If you are concerned about this, or think you may have missed a dose, tell your doctor immediately.

Like all medicines, TORISEL can cause side effects, although not everybody gets them. Side effects may be more pronounced during the higher dose of 175 mg / week during initial treatment for mantle cell lymphoma.

Very common serious side effects observed in more than 1 in 10 patients treated with TORISEL

are:

• Decreased number of white cells in the blood, which may increase your risk of infection.
• Increased blood glucose levels in diabetic and non-diabetic patients.
• Increased blood levels of cholesterol and triglycerides.
• Decreased number of cells in the blood that help the blood to clot, which may increase the risk of bleeding**.

Common serious side effects observed in more than 1 in 100 patients treated with TORISEL are:

• Blood clots in the veins.
• Allergic (hypersensitivity)/infusion reactions (including some life-threatening and rare fatal reactions [rare is less than 1 in 1,000 patients]). You should inform your doctor immediately if you have symptoms of angioedema, such as swollen face, tongue or pharynx, and difficulty in breathing.
• Perforation of the gut (mantle cell lymphoma)*.
• Inflammation of the lungs.
• Kidney failure or kidney problems.
• Problems with wound healing.
• Pleural effusion (fluid around the lungs).

The following side effects and frequencies are those that have been seen in patients treated with TORISEL:

Very Common side effects occurring in more than 1 in 10 patients are:

General feeling of weakness, chills**, swelling due to fluid retention, pain (including abdominal, back, chest and joint pain), feeling or being sick (nausea and vomiting), diarrhoea, fever, sore throat, sores and inflammation in the mouth and/or the digestive tract, cough, upper respiratory infections**, pneumonia**, nose bleed, runny nose, rash, itching, nail disorder, acne, dry skin, anorexia, shortness of breath, low levels of potassium in the blood (which may cause muscle weakness), low red blood cell count, decreased number of white blood cells**, decreased number of lymphocytes**, high blood sugar, high cholesterol and other blood fats, abscess, infections, urinary tract infections, abnormal kidney function (including kidney failure), change in the sense of taste, difficulty falling or staying asleep, anxiety**, muscle pain**.

Common side effects occurring in less than 1 out of 10 patients, but more than 1 per 100 patients, are:

Gum redness and swelling, mouth pain (including sores inside the mouth), stomach bloating, high blood pressure, redness and swelling of the tissues around the eye, including watery eye disorder, taste loss, redness and swelling of the follicles in the skin, allergic (hypersensitivity) reactions, severe scaling of the skin, and problems with healing after surgery, increased blood clotting (including thrombosis of the veins, embolism in the lung), inflammation of the lung, infection in the blood,

dehydration, depression, sleepiness, numbness and tingling of the skin, dizziness, perforation of the gut*, bleeding from the stomach or intestines, inflammation of the lining of the stomach, trouble with swallowing, eye or skin bleeding (bruising), yeast infection, fungal infection of the skin, and blood tests that show changes in the way the liver or kidney are working, low levels of phosphate in the blood, low levels of calcium in the blood.

*occurred as uncommon for renal cell carcinoma
**occurred as common for renal cell carcinoma

Uncommon side effects occurring in less than 1 out of 100 patients, but more than 1 per 1,000 patients are:

Pericardial effusion (fluid around the heart that may require drainage and can affect the pumping of blood).

Bleeding into the brain in patients with brain tumours or who are on blood thinners

Side effects for which frequency has not been determined are:

Swelling of the face, lips, tongue, and throat, possibly causing difficulty breathing.

Serious reactions of the skin and/or mucous membranes which may include painful blisters and fever ( Stevens-Johnson syndrome).

Unexplained muscle pain, tenderness or weakness which could indicate muscle damage ( rhabdomyolysis)

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use TORISEL after the expiry date, which is stated on the vial label and carton. The first two numbers indicate the month; the next four numbers indicate the year.

Store in a refrigerator (2°C-8°C).

Do not freeze.

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

After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the mixture may be stored for up to 24 hours below 25°C and protected from light prior to further dilution.

After further dilution of the concentrate-diluent mixture with sodium chloride 9 mg/ml (0.9%) solution for injection, the solution may be stored for up to 6 hours below 25°C and protected from light.

What TORISEL contains

The active substance is temsirolimus.

Each vial of TORISEL concentrate contains 30 mg of temsirolimus.
The other ingredients in TORISEL are anhydrous ethanol, all- rac-?-tocopherol (E 307), propylene glycol and anhydrous citric acid (E 330). The diluent contains polysorbate 80 (E 433), macrogol 400 and anhydrous ethanol.

What TORISEL looks like and contents of the pack

TORISEL is a concentrate for infusion supplied with a diluent.
The concentrate is a clear, colourless to light-yellow solution. The diluent is a clear to slightly turbid, light-yellow to yellow solution. The solutions are essentially free from visable particulates.

Each pack of TORISEL contains one vial of 1.2 ml concentrate and one vial of 2.2 ml diluent.

Marketing Authorisation Holder

Wyeth Europa Ltd
Huntercombe Lane South
Taplow, Maidenhead
Berkshire SL6 0PH
United Kingdom

Manufacturer

Wyeth Lederle S.p.A.
Via Franco Gorgone
Zona Industriale
95100 Catania, Italy

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

Magyarország Pfizer Kft. Tel. 36 1 488 3700 BelgiëBelgiqueBelgien LuxembourgLuxemburg Pfizer S.A. N.V. TélTel 32 02 554 62 11

eská republika Pfizer s.r.o. Tel 420-283-004-111 Malta Vivian Corporation Ltd. Tel 35621 344610

Danmark Pfizer ApS Tlf 45 44 201 100 Nederland Wyeth Pharmaceuticals B.V. Tel 31 23 567 2567

Deutschland Pfizer Pharma GmbH Tel 49 030 550055-51000 Polska Pfizer Polska Sp. z o.o., Tel 48 22 335 61 00

España Pfizer, S.A. Tel 34 91 490 99 00 Portugal Laboratórios Pfizer, Lda. Tel 351 21 423 55 00

France Pfizer Tél 33 01 58 07 34 40 Slovenská republika Pfizer Luxembourg SARL, organizaná zloka Tel 421 2 3355 5500

Ireland Wyeth Pharmaceuticals SuomiFinland Pfizer Oy

Tel 353 1 449 3500 PuhTel 358 09 430 040

Ísland Icepharma hf. Sími 354 540 8000 Italia Wyeth Lederle S.p.A. Tel 39 06 927151 Sverige Pfizer AB Tel 46 08 550 520 00 Norge Pfizer AS Tlf 47 67 526 100

Pfizer Hellas A.E. T 30 2 10 67 85 800 United Kingdom Wyeth Pharmaceuticals Tel 44 845 367 0098

Wyeth Hellas Cyprus Branch AEBE T 357 22 817690 EestiLatvijaLietuvaSlovenija Wyeth Whitehall Export GmbH Te.TelTãlr 43 1 89 1140

Österreich Pfizer Corporation Austria Ges.m.b.H. Tel 43 01 521 15-0 România Pfizer Romania S.R.L Tel 40 0 21 207 28 00

This leaflet was last approved in

__________________________________________________________________________________

The following information is intended for medical or healthcare professionals only:

During handling and preparation of admixtures, TORISEL should be protected from excessive room light and sunlight.

Bags/containers that come in contact with TORISEL must be made of glass, polyolefin, or polyethylene.

Polyvinyl chloride (PVC) bags and medical devices must not be used for the administration of preparations containing polysorbate 80, because polysorbate 80 leaches di-2-ethylhexylphthalate (DEHP) from PVC.

Dilution

TORISEL 30 mg concentrate must be diluted with 1.8 ml of withdrawn diluent before administration in sodium chloride 9 mg/ml (0.9%) solution for injection.

Note: For mantle cell lymphoma, multiple vials will be required for each dose over 25 mg. Each vial of TORISEL must be diluted according to the instructions below. The required amount of concentrate-diluent mixture from each vial must be combined in one syringe for rapid injection into 250 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

In preparing the solution, the following two-step process must be carried out in an aseptic manner according to local standards for handling cytotoxic/cytostatic drugs:

STEP 1: DILUTION OF CONCENTRATE WITH THE SUPPLIED DILUENT

• Withdraw 1.8 ml of the supplied diluent.
• Inject the 1.8 ml of extracted diluent into the vial of TORISEL 30 mg concentrate.
• Mix the diluent and the concentrate well by inversion of the vial. Sufficient time should be allowed for air bubbles to subside. The solution should be a clear to slightly turbid, colourless to light-yellow to yellow solution, essentially free from visual particulates.

One vial of TORISEL 30 mg concentrate contains 30 mg of temsirolimus: when the 1.2 ml concentrate is combined with 1.8 ml of withdrawn diluent, a total volume of 3.0 ml is obtained and the concentration of temsirolimus will be 10 mg/ml. The concentrate-diluent mixture is stable below 25°C for up to 24 hours.

STEP 2: ADMINISTRATION OF CONCENTRATE-DILUENT MIXTURE IN SODIUM CHLORIDE INFUSION

• Withdraw the required amount of concentrate-diluent mixture (which contains temsirolimus 10 mg/ml) from the vial; i.e., 2.5 ml for a temsirolimus dose of 25 mg.
• Inject the withdrawn volume rapidly into 250 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to ensure adequate mixing.

The admixture should be mixed by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming.

The resulting solution should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. The admixture of TORISEL in sodium chloride 9 mg/ml (0.9%) solution for injection should be protected from excessive room light and sunlight.

For mantle cell lymphoma, multiple vials will be required for each dose over 25 mg.

Administration

• Administration of the final diluted solution should be completed within six hours from the time that the TORISEL is first added to sodium chloride 9 mg/ml (0.9%) solution for injection.
• TORISEL is infused over a 30- to 60-minute period once weekly. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the medicinal product.
• Appropriate administration materials must be composed of glass, polyolefin, or polyethylene to avoid excessive loss of medicinal product and to decrease the rate of DEHP extraction. The administration materials must consist of non-DEHP, non-PVC tubing with appropriate filter. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused. If the administration set available does not have an in-line filter incorporated, a filter should be added at the end of the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended.
• TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This incompatibility has to be considered during the preparation and administration of TORISEL. It is important that the recommendations in sections 4.2 and 6.6 in the SPC be followed closely.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.