Product Information for the Patient

Torisel 30 mg Concentrate and Diluent for Solution for Infusion

temsirolimus

Read this entire product information carefully before you receive this medication, as it contains important information for you.

• Keep this product information, as you may need to refer to it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.

• If you experience any adverse effects, consult your doctor, pharmacist, or nurse,even if they are not listed in this product information. See section 4.

Torisel contains the active ingredient temsirolimus.

Temsirolimus is a selective inhibitor of the mTOR enzyme (mammalian target of rapamycin) that blocks the growth and division of tumor cells.

Torisel is used to treat the following types of cancer in adults:

-Advanced kidney cancer (renal cancer).

-mantle cell lymphoma, a type of cancer that affects lymph nodes, previously treated.

No use Torisel

• if you are allergic to temsirolimus, polysorbate 80, or any of the other ingredients in this medication (listed in section 6);
• if you are allergic to sirolimus (a medication used to prevent the body from rejecting a kidney transplant), since temsirolimus releases sirolimus in the body;
• if you have liver problems and mantle cell lymphoma.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before Torisel is administered to you:

• if you are allergic to antihistamines or cannot use antihistamines for other medical reasons.Antihistamines are administered to help prevent an allergic reaction to Torisel, including some life-threatening and fatal reactions in rare cases. Discuss other alternatives with your doctor;
• if you have or have had brain tumors or spinal cord tumors, bleeding problems, or if you are taking medications to prevent blood clotting (such as warfarin or acenocoumarol).Torisel may increase the risk of bleeding in your brain. Inform your doctor if you are taking anticoagulant medications or have bleeding or bruising while taking Torisel;
• if you have difficulty breathing, coughing, and/or fever.Torisel may weaken your immune system. You may be at risk of contracting blood infections, skin infections, upper respiratory tract infections (including pneumonia), and/or urinary tract infections while taking Torisel. Inform your doctor if you experience new symptoms or worsening of existing symptoms, or if you are taking or have recently taken medications that weaken the immune system;
• if you have or have had lung inflammation.Torisel may cause non-specific interstitial pneumonitis. Some patients had no symptoms or had mild symptoms. Therefore, your doctor may recommend a lung examination by computed tomography or chest X-ray before and during Torisel treatment. Inform your doctor immediately if you experience new respiratory symptoms or if existing symptoms worsen, such as shortness of breath or difficulty breathing;
• if you drink alcohol or are an alcoholic.Torisel contains alcohol and may be harmful to those who drink alcohol or have alcoholism. Inform your doctor if you have alcohol problems or consume alcohol [see the section "Torisel contains ethanol (alcohol)"];
• if you have or have had kidney problems.Your doctor will monitor your renal function;
• if you have or have had liver problems.Inform your doctor if you develop any of the signs and symptoms of liver problems during Torisel treatment: itching, yellow eyes or skin, dark urine, and upper right abdominal pain or discomfort. Your doctor will perform blood tests to check your liver function and may decide to reduce the Torisel dose;
• if you have or have had high cholesterol.Torisel may increase your triglycerides and/or cholesterol, which may require treatment with lipid-lowering agents (medications used to reduce blood cholesterol);
• if you are to undergo surgery or have recently had surgery.Torisel may increase the risk of wound healing problems. Torisel is usually discontinued if you have surgery. Your doctor will decide when to start Torisel again;
• if you plan to be vaccinated during Torisel treatment. Vaccination may be less effective or the use of certain vaccines should be avoided during Torisel treatment;
• if you are over 65 years old. You may be more likely to experience certain adverse effects, such as facial swelling, diarrhea, pneumonia, anxiety, depression, difficulty breathing, decreased white blood cell count, muscle pain, taste disturbance, upper respiratory tract infection, pleural effusion, mouth and/or gastrointestinal inflammation, nasal secretion, dizziness, and infections;
• Torisel may increase blood glucose levels and worsen diabetes mellitus.This may result in the need for insulin and/or oral antidiabetic medication. Consult your doctor if you experience excessive thirst or an increase in the frequency and amount of urination;
• Torisel may decrease the number of blood cells that help with clotting and resist infections,which may increase the risk of bleeding/bruising and infections (see the section "Possible adverse effects");
• if you have or have had eye problems such as cataracts.Your doctor may prescribe a visual examination before or during Torisel treatment;
• if you are receiving Torisel, you may be at a higher risk of cancer, such as skin cancer and lymphoma;
• if you are receiving Torisel, you may be at a higher risk of heart attack. Inform your doctor if you experience symptoms such as chest pain or pressure, arm, shoulder, or jaw pain, difficulty breathing, nausea, anxiety, sweating, or dizziness;

If you have any doubts, consult your doctor, pharmacist, or nurse.

Children and adolescents

This medication is not for children or adolescents under 18 years old since advanced kidney cancer and mantle cell lymphoma are not significant diseases in these patients, and this medication is not effective for other types of cancer.

Other medications and Torisel

Inform your doctor or pharmacist if you are taking or have recently taken any other medication.

Some medications may interfere with the breakdown or metabolism of Torisel and may require adjustment of the Torisel dose. In particular, you should inform your doctor or pharmacist if you are taking any of the following:

• protease inhibitors, used in the treatment of HIV;
• antibiotics (such as rifampicin) or antifungals (including itraconazole, ketoconazole, and voriconazole) for the treatment of infections;
• nefazodone or selective serotonin reuptake inhibitors, used for the treatment of depression;
• antiepileptic medications, such as carbamazepine, phenytoin, and phenobarbital;
• rifabutin, used for the treatment of infections in people with HIV and other diseases;
• herbal remedies or natural remedies containing St. John's Wort (Hypericum perforatum, hypericum) used for the treatment of mild depression;
• angiotensin-converting enzyme inhibitors (ACEIs) (such as enalapril, ramipril, lisinopril) or calcium channel blockers (such as amlodipine), used for the treatment of hypertension or other cardiovascular problems;
• amiodarone, used for the treatment of arrhythmias, or statins used to treat high cholesterol;
• sunitinib, used to treat kidney cancer;
• medications that are substrates of the gp-P (such as digoxin, vincristine, colchicine, dabigatran, lenalidomide, paclitaxel);
• cannabidiol (its use includes, among others, the treatment of epilepsy).

Use of Torisel with food and beverages

Orange and orange juice may increase the concentration of Torisel in the blood and should be avoided.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor before using this medication.

Torisel has not been studied in pregnant women and should not be used during pregnancy, unless clearly necessary.

Women of childbearing potential should avoid pregnancy using an effective contraceptive method during Torisel treatment. Men with potentially fertile partners should use a medically acceptable contraceptive method during Torisel treatment.

Women should not breastfeed during Torisel treatment, as this medication may interfere with the growth and development of the baby.

Torisel contains alcohol (ethanol). If you are pregnant or breastfeeding, you should consult your doctor or pharmacist before taking this medication.

Torisel contains propylene glycol. If you are pregnant, do not take this medication unless recommended by your doctor (see "Torisel contains propylene glycol"). Propylene glycol may pass into breast milk. If you are breastfeeding, do not take this medication unless recommended by your doctor (see "Torisel contains propylene glycol").

Driving and operating machinery

Torisel is unlikely to affect your ability to drive and operate machinery. However, nausea and vomiting, and difficulty falling asleep or staying asleep are very common adverse effects. If you experience nausea and vomiting, or difficulty falling asleep or staying asleep, be extra careful when driving or operating machinery.

In patients receiving the highest dose of Torisel for mantle cell lymphoma treatment, the amount of alcohol in this medication may decrease your ability to drive or operate machinery (see the section "Torisel contains ethanol [alcohol]" below).

Torisel contains alcohol (ethanol)

This medication contains alcohol (ethanol), equivalent to 18ml of beer or 7ml of wine per 25mg dose. Patients receiving the highest dose of 175mg of Torisel for initial mantle cell lymphoma treatment may receive a dose of ethanol equivalent to up to 122ml of beer or 49ml of wine per dose. This medication is harmful if you have alcoholism. The alcohol content should be taken into account in the case of pregnant women, breastfeeding women, children, and high-risk groups, such as patients with liver disease or epilepsy.

Torisel is unlikely to have any perceptible effect on adults or adolescents. It may have some effects on infants and young children, such as drowsiness. If you have a history of alcohol addiction, consult your doctor or pharmacist before taking this medication.

The amount of alcohol in this medication may alter the effect of other medications. Consult your doctor or pharmacist if you are taking other medications.

The amount of alcohol in this medication may impair your ability to drive or alter the effects of other medications (see the sections "Warnings and precautions" and "Driving and operating machinery").

Torisel contains propylene glycol

Torisel contains 503.3mg of propylene glycol in each 25mg dose, equivalent to 201.33mg/ml of the diluted product. If the child is under 5 years old, consult your doctor or pharmacist, especially if other medications containing propylene glycol or alcohol are being administered. If you are pregnant or breastfeeding, or if you have liver or kidney problems, do not take this medication unless recommended by your doctor. Your doctor may perform additional checks while you are taking this medication.

Torisel must always be prepared and administered by a doctor or other healthcare professional in the form of an intravenous infusion (through a vein).

An antihistamine (to try to prevent allergic reactions to Torisel) must be injected directly into a vein, approximately 30 minutes before the dose of Torisel.

The Torisel concentrate must be diluted first with 1.8 ml of the provided solvent to achieve a concentration of 10 mg/ml before administration in a sodium chloride 9 mg/ml (0.9%) injectable solution (see dilution instructions at the end of the leaflet).

The recommended dose for renal cancer is 25 mg, infused (dripped) over a period of 30 to 60 minutes, once a week.

The recommended dose for mantle cell lymphoma is 175 mg, infused (dripped) over a period of 30 to 60 minutes, once a week for 3 weeks, followed by single weekly doses of 75 mg infused (dripped) over a period of 30 to 60 minutes.

Treatment with Torisel should continue until no more benefits from treatment are obtained or until unacceptable side effects appear.

Since this medication is prepared and administered by a healthcare professional, it is unlikely that you will receive too large a dose or forget a dose.

However, if you have any doubts, consult your doctor immediately.

If you have any other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Side effects may be more pronounced with the higher dose of 175mg per week, during the initial treatment of mantle cell lymphoma.

The most important side effects that you may experience during treatment with Torisel are listed below. If you experience any of them, seek medical attention immediately.

Allergic reactions

You shouldcontact your doctor or nurse immediatelyif you experience symptoms of angioedema, such as swelling of the face, tongue, or throat, and difficulty breathing.

If you experience any of these symptoms during the administration of Torisel, your doctor or nurse will stop the infusion.

Cerebral hemorrhage

You shouldcontact your doctor immediatelyif you feel confused, are more tired than usual, have difficulty speaking or swallowing, and your pupils are of different sizes. These symptoms may be caused by a cerebral hemorrhage.

Intestinal puncture, tears, or perforations

You shouldcontact your doctor immediatelyif you experience severe abdominal pain, high fever, nausea, or vomiting, or blood in your stool. These symptoms may be caused by an intestinal perforation.

Renal failure

You shouldcontact your doctor immediatelyif you experience general swelling, shortness of breath, fatigue. These symptoms may be caused by a sudden decrease in renal function.

Pulmonary embolism

You shouldcontact your doctor immediatelyif you experiencedifficulty breathing, chest pain, coughing up blood, rapid heart rate, nausea, dizziness, sweating, wheezing, blue or sticky skin. These symptoms may be caused by a pulmonary embolism.

You should also inform your doctor immediately:

• if you experience coughing, chest pain, difficulty breathing. Your doctor may perform a chest X-ray examination;
• if you have a decrease in the number of white blood cells in your blood. This may increase the risk of fever and infections;
• if you have a decrease in the number of platelets (a type of blood cell that helps in blood clotting). This may increase the risk of bleeding in your body;
• if your cholesterol and triglyceride levels in the blood have increased;
• if you experience excessive thirst or an increase in the frequency and amount of urine. Your doctor may prescribe insulin and/or oral antidiabetic medication;
• if you have recently undergone surgery. Your doctor may delay the administration of Torisel until the wound is fully healed, as this medicine may interfere with the healing of existing wounds.

Other side effects associated with Torisel may include:

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

General feeling of weakness, chills, fluid retention, pain (including abdominal, back, chest, and joint pain), feeling unwell (nausea and vomiting), diarrhea, constipation, headache, fever, mouth sores and inflammation in the digestive tract, coughing, pneumonia, nasal bleeding, skin rash, itching, dry skin, loss of appetite, difficulty breathing, decrease in potassium levels in the blood (which may cause muscle weakness), decrease in red blood cell count, decrease in a type of white blood cell in the blood, which is associated with an increased risk of infections, elevated blood sugar, elevated cholesterol, elevated triglycerides, abscess, infections (including eye infections, flu, viral infections, bronchitis), abnormal kidney function (including renal failure), abnormal blood tests showing changes in kidney function, taste disturbance, difficulty falling asleep, decrease in platelet count, which may cause bleeding and petechiae.

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

Nasal discharge, redness and swelling of the gums, mouth pain (including mouth sores), abdominal distension, sore throat, elevated blood pressure, red eye including a disturbance in tear production, loss of taste, redness and inflammation of the skin follicles, allergic reactions, intense skin peeling, increased blood clotting (including venous thrombosis), low calcium levels in the blood, low phosphate levels in the blood, upper respiratory tract infections, pulmonary inflammation, fluid in the thoracic cavity, blood infection, dehydration, excitement, depression, feeling of numbness and tingling in the skin, dizziness, somnolence, bleeding (in the lips, mouth, stomach, or intestines), inflammation of the mucous membrane covering the stomach, swallowing difficulties, bleeding in the skin (petechiae), small punctate bleeding, nail problems, acne, fungal infections, urinary tract infections, cystitis, abnormal blood test results showing changes in liver function, elevated fats in the blood other than triglycerides, diabetes, muscle pain.

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

Pericardial effusion (fluid around the heart, which may require drainage and may affect blood pumping).

Cerebral hemorrhage in patients with brain tumors or those taking anticoagulants, eye hemorrhage.

Pulmonary embolism, intestinal perforation, problems with wound healing after surgery, inflammation and swelling of the larynx.

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

Pneumocystis jiroveci pneumonia (pneumonia caused by Pneumocystis jiroveci).

Side effects of unknown frequency (cannot be estimated from available data):

Swelling of the face, lips, tongue, and throat, which may cause difficulty breathing.

Severe skin and/or mucous membrane reactions, which may include painful blisters and fever (Stevens-Johnson syndrome).

Muscle pain of unknown origin, sensitivity or weakness, which may indicate muscle damage (rhabdomyolysis).

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet.You can also report them directly through the Spanish System for the Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the vial label and on the case. The expiration date is the last day of the month indicated.

Store in refrigerator (between 2°C and 8°C).

Do not freeze.

Store vials in the outer packaging to protect them from light.

After the first dilution of the concentrate with 1.8 ml of the provided solvent, the mixture can be stored for a maximum of 24 hours below 25°C and protected from light, before new dilutions.

After the subsequent dilution of the concentrate-solvent mixture with sodium chloride injection 9 mg/ml (0.9%), the solution can be stored for a maximum of 6 hours below 25°C and protected from light.

Medicines should not be disposed of through drains. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Composition of Torisel

• The active ingredient is temsirolimus.

Each vial of concentrate contains 30mg of temsirolimus.

After the first dilution of the concentrate with 1.8ml of the supplied solvent, the concentration of temsirolimus is 10mg/ml.

• The other components of the concentrate are: anhydrous ethanol, all-rac-?-tocopherol (E 307), propylene glycol (E 1520), and citric acid (E 330). The solvent contains polysorbate 80 (E 433), macrogol 400, and anhydrous ethanol (see section 2 “Torisel contains alcohol [ethanol]” and “Torisel contains propylene glycol”).

Appearance of the product and contents of the pack

Torisel is a concentrate and solvent for solution for infusion.

The concentrate is a transparent, colorless, or pale yellow solution. The solvent is a transparent or slightly turbid, pale yellow, or yellow solution. The solutions are practically free of visible particles.

Each pack of Torisel contains a glass vial with 1.2ml of concentrate and a glass vial with 2.2ml of solvent.

Marketing Authorization Holder

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Brussels

Belgium

Responsible for manufacturing

Wyeth Lederle S.r.l.

Via Franco Gorgone

Industrial Zone

95100 Catania

Italy

For more information about this medicinal product, please contact the local representative of the marketing authorization holder:

Spain

Pfizer, S.L.

Phone: +34 91 490 99 00

Last update of this leaflet:

Other sources of information

The detailed information on this medicinal product is available on the website of the European Medicines Agency:http://www.ema.europa.eu.There are also links to other websites on rare diseases and orphan medicines.

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This information is intended for healthcare professionals only:

During the manipulation and preparation of the mixtures, Torisel must be protected from excessive ambient light and sunlight.

The bags/packs that come into contact with Torisel must be made of glass, polyolefin, or polyethylene.

Do not use bags and medical devices made of PVC for the administration of preparations containing polysorbate 80, as polysorbate 80 leaches DEHP from PVC.

The concentrate and solvent of Torisel must be visually inspected before administration to discard the presence of particles or color change.

Do not use if there are particles or color change. Use a new vial.

Dilution

The concentrate for solution for infusion must be diluted with the supplied solvent before administration in a sodium chloride 9mg/ml (0.9%) solution.

Nota: In mantle cell lymphoma, several vials are needed for each dose above 25mg. Each vial of Torisel must be diluted according to the instructions that are indicated below. The amount of concentrate-solvent mixture from each vial must be combined in a syringe for rapid injection in 250ml of sodium chloride 9mg/ml (0.9%) solution.

The concentrate-solvent mixture must be visually inspected to discard the presence of particles or color change.

Do not use if there are particles or color change.

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

STEP 1: DILUTION OF THE CONCENTRATE FOR SOLUTION FOR INFUSION WITH THE SUPPLIED SOLVENT

• Extract 1.8ml of the supplied solvent.
• Inject the 1.8ml of solvent into the Torisel 30mg concentrate vial.
• Mix the solvent and concentrate well by inverting the vial. Allow sufficient time for the air bubbles to disappear. The solution must be transparent or slightly turbid, colorless, or pale yellow, or yellow, and practically free of visible particles.

One vial of Torisel concentrate contains 30mg of temsirolimus: when the 1.2ml of concentrate is combined with the 1.8ml of supplied solvent, a total volume of 3.0ml is obtained, with a temsirolimus concentration of 10mg/ml. The concentrate-solvent mixture remains stable below 25?°C for a maximum of 24hours.

STEP 2: ADMINISTRATION OF THE CONCENTRATE FOR SOLUTION FOR INFUSION-SOLVENT MIXTURE IN SODIUM CHLORIDE 9mg/ml (0.9%) SOLUTION

• Extract the required amount of concentrate-solvent mixture (containing temsirolimus 10mg/ml) from the vial; i.e., 2.5ml for a temsirolimus dose of 25mg.
• Inject the extracted volume rapidly into 250ml of sodium chloride 9mg/ml (0.9%) solution to ensure proper mixing.

The final diluted solution in the bag or bottle must be visually inspected to discard the presence of particles or color change before administration. The Torisel mixture in sodium chloride 9mg/ml (0.9%) solution must be protected from excessive ambient light and sunlight.

In mantle cell lymphoma, several vials are needed for each dose above 25mg.

Administration

• The administration of the final diluted solution must be completed within 6hours from the moment of the first addition of Torisel to the sodium chloride 9mg/ml (0.9%) solution.
• Torisel is infused over a period of 30 to 60minutes once a week. The preferred method of administration is the use of an infusion pump, in order to ensure the precise administration of the drug.
• Materials for administration must be used to avoid excessive loss of the active principle and to reduce the rate of extraction of DEHP. Materials for administration must consist of tubing without DEHP or PVC, with a suitable filter. For administration, a filter of polyethersulfone in line with a pore size not greater than 5microns is recommended, to avoid the possibility of infusing particles larger than 5microns. If the available administration set does not have an in-line filter, a filter must be added to the end of the set (i.e., an end filter) before the mixture reaches the patient's vein. Different end filters with pore sizes ranging from 0.2microns to 5microns can be used. The use of an in-line filter and an end filter is not recommended.
• Torisel, after dilution, contains polysorbate 80 and therefore, suitable materials for administration must be used. It is essential to follow the recommendations in sections 4.2 and 6.6 of the SmPC.

Elimination

The unused medicinal product and all materials that have come into contact with it will be disposed of in accordance with local regulations.