TORISEL 30 mg Concentrate and Diluent for Solution for Infusion

Introduction

Package Leaflet: Information for the Patient

Torisel 30mg concentrate and solvent for solution for infusion

temsirolimus

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.

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

Contents of the pack

1. What Torisel is and what it is used for
2. What you need to know before you are given Torisel
3. How Torisel is administered
4. Possible side effects
5. Storage of Torisel
6. Contents of the pack and further information

1. What Torisel is and what it is used for

Torisel contains the active substance temsirolimus.

Temsirolimus is a selective inhibitor of the enzyme mTOR (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 cell carcinoma).
• Mantle cell lymphoma, a type of cancer that affects the lymph nodes, which has been previously treated.

2. What you need to know before you are given Torisel

Do not use Torisel

• if you are allergic to temsirolimus, polysorbate 80, or any of the other ingredients of this medicine (listed in section 6);
• if you are allergic to sirolimus (a medicine used to prevent the body from rejecting a kidney transplant), as 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 you are given Torisel:

• if you are allergic to antihistamines or cannot use antihistaminesfor other medical reasons. Antihistamines are given to help prevent an allergic reaction to Torisel, including some life-threatening and fatal allergic reactions in rare cases. Discuss other alternatives with your doctor;
• if you have or have had tumors in the brain or spinal cord, bleeding problems or bruising, or if you are taking medicines 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 medicines or have bleeding or bruising while being treated with Torisel;
• if you have difficulty breathing, coughing, and/or fever.Torisel may weaken your immune system. You may be at risk of contracting a blood infection, skin infection, upper respiratory tract infection (including pneumonia), and/or urinary tract infection while being treated with Torisel. Inform your doctor if you experience new symptoms or if your existing symptoms worsen, or if you are taking or have recently taken medicines that weaken the immune system;
• if you have or have had inflammation in the lungs.Torisel may cause non-specific interstitial pneumonitis. Some patients may not have symptoms or may have minimal symptoms. For this reason, your doctor may recommend a lung examination by computed tomography or chest X-ray before and during treatment with Torisel. Inform your doctor immediately of any new respiratory symptoms or if your 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 a history of alcoholism. Inform your doctor if you have problems with alcohol or consume alcohol [see the section "Torisel contains ethanol (alcohol)"];
• if you have or have had kidney problems.Your doctor will monitor your kidney function;
• if you have or have had liver problems.Inform your doctor if you develop any signs or symptoms of liver problems during treatment with Torisel: itching, yellowing of the eyes or skin, dark urine, and pain or discomfort in the upper right abdomen. Your doctor will perform blood tests to check your liver function and may decide to reduce the dose of Torisel;
• if you have or have had high cholesterol.Torisel may increase your triglycerides and/or cholesterol, which may require treatment with lipid-lowering agents (medicines used to lower cholesterol in the blood);
• if you are going to have surgery or have had surgery recently.Torisel may increase the risk of wound healing problems. Torisel will usually be stopped if you have surgery. Your doctor will decide when to restart Torisel;
• if you are planning to be vaccinated during treatment with Torisel. Vaccination may be less effective or the use of certain vaccines should be avoided during treatment with Torisel;
• if you are over 65 years of age. You may be more likely to experience certain side effects, such as facial swelling, diarrhea, pneumonia, anxiety, depression, difficulty breathing, decreased white blood cell count, muscle pain, taste disorder, upper respiratory tract infection, fluid accumulation around the lungs, ulcers, and inflammation of the mouth and/or digestive tract, nasal discharge, dizziness, and infections;
• Torisel may increase blood sugar levels and worsen diabetes mellitus.This may result in the need for insulin and/or oral antidiabetic treatment. Consult your doctor if you experience excessive thirst or an increase in the frequency and amount of urine;
• Torisel may decrease the number of blood cells that help with blood clotting and fight infections,which may increase the risk of bleeding/bruising and infections (see section "Possible side effects");
• if you have or have had eye problems such as cataracts.Your doctor may prescribe an eye examination before or during treatment with Torisel;
• if you are receiving Torisel, you may be at a higher risk of cancer, such as skin cancer and lymph node cancer (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, feeling sick (nausea), anxiety, sweating, or dizziness.

If you have any further questions, ask your doctor, pharmacist, or nurse.

Children and adolescents

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

Other medicines and Torisel

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

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

• protease inhibitors, used to treat the human immunodeficiency virus (HIV)
• antibiotics (such as rifampicin) or antifungals (including itraconazole, ketoconazole, and voriconazole) for the treatment of infections
• nefazodone or selective serotonin reuptake inhibitors, used to treat depression
• antiepileptic medicines, such as carbamazepine, phenytoin, and phenobarbital
• rifabutin, used to treat infections 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 inhibitors (ACE inhibitors) (such as enalapril, ramipril, lisinopril) or calcium channel blockers (such as amlodipine), used to treat high blood pressure or other cardiovascular problems
• amphiphilic medicines, used to treat cardiac arrhythmias (such as amiodarone), or statins used to treat high cholesterol
• sunitinib, used to treat kidney cancer
• medicines that are substrates of P-glycoprotein (such as digoxin, vincristine, colchicine, dabigatran, lenalidomide, paclitaxel)
• cannabidiol (its use includes, among others, the treatment of epileptic seizures).

Using Torisel with food and drinks

Grapefruit and grapefruit juice may increase the concentration of Torisel in the blood and should be avoided.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before taking this medicine.

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

Women of childbearing potential should avoid becoming pregnant by using an effective method of contraception during treatment with Torisel. Men with female partners of childbearing potential should use a medically acceptable method of contraception during treatment with Torisel.

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

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

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

Driving and using machines

Torisel is unlikely to affect your ability to drive or use machines. However, feeling sick (nausea and vomiting) and difficulty sleeping or staying asleep are very common side effects. If you feel sick (nausea and vomiting) or have difficulty sleeping or staying asleep, be careful when driving or operating machinery.

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

Torisel contains alcohol (ethanol)

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

It is unlikely that the amount of alcohol in this medicine will have a noticeable effect on adults or adolescents. It may have some effects on babies and young children, such as drowsiness. If you have an alcohol addiction, consult your doctor or pharmacist before taking this medicine.

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

The amount of alcohol in this medicine may impair your ability to drive or alter the effects of other medicines (see sections "Warnings and precautions" and "Driving and using machines").

Torisel contains propylene glycol

Torisel contains 503.3 mg of propylene glycol per 25 mg dose, equivalent to 201.33 mg/ml of the diluted product. If the child is under 5 years of age, consult your doctor or pharmacist, particularly if they are taking other medicines that contain propylene glycol or alcohol. If you are pregnant or breastfeeding, or have liver or kidney failure, do not take this medicine unless advised by your doctor. Your doctor may perform additional checks while you are taking this medicine.

3. How Torisel is administered

Torisel should always be prepared and administered by a doctor or other healthcare professional as an intravenous infusion (in a vein).

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

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

In kidney cancer, the recommended dose is 25 mg, infused over a period of 30 to 60 minutes, once a week.

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

Treatment with Torisel should continue until there are no more benefits from the treatment or until unacceptable side effects occur.

Since this medicine is prepared and administered by a healthcare professional, it is unlikely that you will receive too much or miss a dose.

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

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

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

The most important adverse effects that you may experience during treatment with Torisel are listed below. If you experience any of them, consult your doctor immediately.

Allergic Reactions

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

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

Stroke

You should contact your doctor immediatelyif you feel confused, more tired than usual, have difficulty speaking or swallowing, and your pupils are of different sizes. These symptoms may be caused by a stroke in the brain.

Intestinal Perforation, Tears, or Ruptures

You should contact your doctor immediatelyif you experience acute abdominal pain, high fever, nausea or vomiting, or blood in your stool. These symptoms may be caused by a perforation in the intestine.

Kidney Failure

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

Pulmonary Embolism

You should contact your doctor immediatelyif you experience difficulty breathing, chest pain, coughing up blood, rapid heartbeat, nausea, fainting, sweating, wheezing, blue-tinged skin, or sticky skin. These symptoms may be caused by a blood clot in the lung.

You should also inform your doctor immediately:

• if you have a cough, chest pain, or difficulty breathing. Your doctor may perform a chest X-ray;
• if you have a decreased number of white blood cells in your blood. This may increase the risk of fever and infections;
• if you have a decreased number of platelets (a type of blood cell that helps with blood clotting). This may increase the risk of bleeding in your body;
• if your cholesterol and triglyceride levels have increased in your blood;
• if you are excessively thirsty or have an increased frequency and amount of urine. Your doctor may prescribe insulin and/or oral anti-diabetic medication;
• if you have recently undergone surgery. Your doctor may delay the administration of Torisel until the wound is completely healed, as this medicine may interfere with the wound healing process.

Other Adverse Effects with Torisel may include:

Very Common Adverse Effects (may affect more than 1 in 10 people):

General feeling of weakness, chills, swelling due to fluid retention, pain (including abdominal, back, chest, and joint pain), feeling sick to the stomach (nausea and vomiting), diarrhea, constipation, headache, fever, sores and inflammation in the mouth and/or digestive tract, cough, pneumonia, nosebleeds, skin rash, itching, dry skin, loss of appetite, difficulty breathing, decreased potassium levels in the blood (which may cause muscle weakness), decreased red blood cell count, decreased white blood cell count, 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 kidney failure), blood tests showing changes in kidney function, taste disorder, difficulty sleeping, decreased platelet count, which may lead to bleeding and bruising.

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

Nasal discharge, redness and swelling of the gums, mouth pain (including sores in the mouth), abdominal distension, sore throat, elevated blood pressure, red eye including a tearing disorder, loss of taste, redness and inflammation of skin follicles, allergic reactions, intense skin peeling, increased blood coagulation (including thrombosis in the veins), low calcium levels in the blood, low phosphate levels in the blood, upper respiratory tract infections, lung inflammation, fluid in the thoracic cavity, blood infection, dehydration, excitement, depression, feeling of numbness and tingling in the skin, dizziness, drowsiness, bleeding (in the lips, mouth, stomach, or intestine), inflammation of the mucous membrane lining the stomach, swallowing problems, skin bleeding (bruising), small pinpoint bleeding, nail problems, acne, yeast infection, fungal infection, urinary tract infections, cystitis, blood test results showing altered liver function, increased fat in the blood other than triglycerides, diabetes, muscle pain.

Uncommon Adverse 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 undergoing anticoagulant treatment, bleeding in the eye.

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

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

Pneumocystis jiroveci pneumonia (Pneumocystis jiroveci-induced pneumonia).

Adverse 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 Adverse Effects

If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are possible adverse effects not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Torisel

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

Do not use this medicine after the expiration date stated on the label of the vial and on the carton. The expiration date is the last day of the month indicated.

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

Do not freeze.

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

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

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

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Package Contents and Additional Information

Torisel Composition

• The active ingredient is temsirolimus.

Each vial of concentrate contains 30 mg of temsirolimus.

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

• The other components of the concentrate are: anhydrous ethanol, all-rac-α-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 Package Contents

Torisel is a concentrate and solvent for solution for infusion.

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

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

Marketing Authorization Holder

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Brussels

Belgium

Manufacturer

Wyeth Lederle S.r.l.

Via Franco Gorgone

Zona Industriale

95100 Catania

Italy

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Spain

Pfizer, S.L.

Tel: +34 91 490 99 00

Date of the Last Revision of this Leaflet:

Other Sources of Information

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

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This information is intended only for healthcare professionals:

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

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

PVC (polyvinyl chloride) bags and medical devices should not be used for the administration of preparations containing polysorbate 80, as polysorbate 80 leaches di-(2-ethylhexyl) phthalate (DEHP) from PVC.

The Torisel concentrate and solvent should be visually inspected before administration to rule out the presence of particles or color change.

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

Dilution

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

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

The concentrate-solvent mixture should be visually inspected to rule out the presence of particles or color change.

Do not use if particles or color change are present.

In the preparation of the solution, the following two-step process should be carried out aseptically according to local guidelines for the handling of cytotoxic/cytostatic medicines:

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

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

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

STEP 2: ADMINISTRATION OF THE CONCENTRATE-SOLVENT MIXTURE IN SODIUM CHLORIDE 9 MG/ML (0.9%) INJECTABLE SOLUTION

• Withdraw the required amount of concentrate-solvent mixture (containing 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%) injectable solution to ensure adequate mixing.

The solution should be mixed by inverting the bag or bottle, avoiding excessive agitation, as this may cause foam formation.

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

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

Administration

• The administration of the final diluted solution should be completed within 6 hours of the first addition of Torisel to the sodium chloride 9 mg/ml (0.9%) injectable solution.
• Torisel is infused over a period of 30 to 60 minutes once a week. The preferred method of administration is the use of an infusion pump to ensure precise administration of the medicine.
• Appropriate administration materials should be used to avoid excessive loss of the active ingredient and reduce the extraction rate of DEHP. Administration materials should consist of DEHP-free and PVC-free tubing with an appropriate filter. For administration, a polyethersulfone in-line filter with a pore size of no more than 5 microns is recommended to prevent the infusion of particles larger than 5 microns. If the available administration set does not have an in-line filter, a filter should 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 0.2 microns to 5 microns 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, appropriate administration materials should be used. It is important to carefully follow the recommendations in sections 4.2 and 6.6 of the Summary of Product Characteristics.

Elimination

The elimination of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.