Torisel 30 mg concentrate and solvent for solution for infusion: detailed information

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

Torisel 30mg concentrate and solvent for solution for infusion

temsirolimus

Read the entire leaflet carefully before you are given this medicine, because it contains important information for you.

Keep this leaflet, as you may need to read it again.
If you have any questions, ask your doctor, pharmacist or nurse.
If you experience any adverse reactions, consult your doctor, pharmacist or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Contents of the leaflet

What Torisel is and what it is used for
What you need to know before being given Torisel
How Torisel is administered
Possible side effects
How to store Torisel
Contents of the pack and other 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), which 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 affecting 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), since temsirolimus releases sirolimus in the body;
if you have liver problems and mantle cell lymphoma.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you are given Torisel:

if you are allergic to antihistamines or cannot use antihistamines for 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 alternative options with your doctor;
if you have or have had brain or spinal cord tumors, 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 if you experience bleeding or bruising while being treated with Torisel;
if you have difficulty breathing, cough, and/or fever. Torisel may weaken your immune system. You may be at risk of developing blood, skin, upper respiratory tract (including pneumonia), and/or urinary tract infections while being treated with Torisel. Inform your doctor if you develop new symptoms or if 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 nonspecific interstitial pneumonitis. Some patients may have no symptoms or only mild symptoms. For this reason, your doctor may recommend a lung scan using computed tomography or chest X-ray before and during treatment with Torisel. Immediately inform your doctor of any 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 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, or pain or discomfort in the upper right area of the stomach. 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 levels, which may require treatment with lipid-lowering agents (medicines used to reduce cholesterol in the blood);
if you are scheduled for surgery or have recently had surgery. Torisel may increase the risk of wound healing problems. Torisel is usually stopped if you undergo surgery. Your doctor will decide when to restart treatment;
if you plan to be vaccinated during treatment with Torisel. Vaccination may be less effective, or 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 adverse effects, such as facial swelling, diarrhea, pneumonia, anxiety, depression, difficulty breathing, decreased white blood cell count, muscle pain, taste disturbances, upper respiratory tract infection, fluid accumulation around the lungs, mouth sores and inflammation of the mouth and/or digestive tract, nasal discharge, dizziness, and infections;
Torisel may increase blood glucose levels and worsen diabetes mellitus. This may result in the need for treatment with insulin and/or oral antidiabetic medicines. Consult your doctor if you experience excessive thirst or increased frequency and volume of urination;
Torisel may decrease the number of blood cells that help with 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 a vision examination before or during treatment with Torisel;
if you are receiving Torisel, you may have an increased risk of cancer, such as skin cancer and lymph node cancer (lymphoma);
if you are receiving Torisel, you may have an increased 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 unwell (nausea), anxiety, sweating, or dizziness.

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

Children and adolescents

This medicine is not intended for children or 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 therefore a dose adjustment of Torisel may be necessary. In particular, inform your doctor or pharmacist if you are taking any of the following:

protease inhibitors, used in the treatment of human immunodeficiency virus (HIV)
antibiotics (such as rifampicin) or antifungals (including itraconazole, ketoconazole, and voriconazole) used to treat 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, hypericum) 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-gp (such as digoxin, vincristine, colchicine, dabigatran, lenalidomide, paclitaxel)
cannabidiol (its uses include, among others, treatment of epileptic seizures).

Use of 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 plan to become pregnant, consult your doctor before using 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 pregnancy by using an effective contraceptive method during treatment with Torisel. Men with partners of childbearing potential should use a medically appropriate contraceptive method during treatment with Torisel.

Women must not breastfeed during treatment with Torisel, as this medicine may interfere with the baby’s growth and development.

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

Torisel contains propylene glycol. If you are pregnant, do not take this medicine 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 medicine unless recommended by your doctor (see “Torisel contains propylene glycol”).

Driving and using machines

It is unlikely that Torisel will affect your ability to drive or use machines. However, feeling unwell (nausea and vomiting), and difficulty falling asleep or staying asleep are very common side effects. If you feel unwell (nausea and vomiting), or have difficulty falling or staying asleep, take special care 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 reduce your ability to drive or use machines (see section “Torisel contains ethanol [alcohol]” below).

Torisel contains alcohol (ethanol)

This medicine contains alcohol (ethanol), in an amount 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 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 considered in pregnant or breastfeeding women, children, and high-risk groups, such as patients with liver disease or epilepsy.

The amount of alcohol in this medicine is unlikely to have any noticeable effect in adults or adolescents. It could have some effects in infants and young children, such as drowsiness. If you are alcohol-dependent, consult your doctor or pharmacist before taking this medicine.

The amount of alcohol contained 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 in each 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 receiving other medications containing propylene glycol or alcohol. If you are pregnant or breastfeeding, or if you have hepatic or renal impairment, do not take this medicine unless recommended by your doctor. Your doctor may carry out additional monitoring while you are taking this medicine.

3. How Torisel is administered

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

An antihistamine (to help prevent allergic reactions to Torisel) should be injected into a vein approximately 30 minutes before the dose of Torisel.

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

In renal cancer, the recommended dose is 25 mg, infused (by drip) over a period of 30 to 60 minutes, once a week.

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

Treatment with Torisel should continue until no further benefit from treatment is observed 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 high a dose or miss a dose.

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

If you have any further questions about 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 everyone will experience them.

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

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

Allergic reactions

You must contact your doctor or nurse immediately if you develop symptoms of angioedema, such as swelling of the face, tongue, or throat, and difficulty breathing.

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

Stroke

You must contact your doctor immediately if you feel confused, more tired than usual, have difficulty speaking or swallowing, or have pupils of unequal size. These symptoms may be caused by a stroke in the brain.

Intestinal perforation, tears, or perforations

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

Pulmonary embolism

You must contact your doctor immediately if you experience difficulty breathing, chest pain, coughing up blood, rapid heartbeat, nausea, fainting, sweating, wheezing, or bluish or clammy skin. These symptoms may be caused by a blood clot in the lung.

You should also contact your doctor immediately if:

you develop cough, chest pain, or difficulty breathing. Your doctor may perform a chest X-ray examination;
you have a decreased number of white blood cells in your blood. This may increase the risk of fever and infections;
you have a decreased number of platelets (a type of blood cell that helps blood to clot). This may increase the risk of bleeding in your body;
your blood cholesterol and triglyceride levels have increased;
you have excessive thirst or increased frequency and volume of urination. Your doctor may prescribe insulin and/or oral antidiabetic medication;
you have recently undergone surgery. Your doctor may delay administration of Torisel until the wound is completely healed, as this medicine may interfere with the healing process of existing wounds.

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, mouth 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 blood (which may cause muscle weakness), decreased red blood cell count, decreased count of a type of white blood cells associated with 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 disturbance, difficulty sleeping, decreased platelet count which may lead to bleeding and bruising.

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

Runny nose, redness and swelling of gums, mouth pain (including sores inside the mouth), abdominal distension, sore throat, elevated blood pressure, red eye including a disorder of tearing, loss of taste, redness and inflammation of skin follicles, allergic reactions, severe skin peeling, increased blood clotting (including venous thrombosis), low calcium levels in blood, low phosphate levels in blood, upper respiratory tract infections, lung inflammation, fluid in the chest cavity, blood infection, dehydration, restlessness, depression, sensation of numbness and tingling in the skin, dizziness, drowsiness, bleeding (in lips, mouth, stomach, or intestine), inflammation of the mucosa lining the stomach, difficulty swallowing, bleeding in the skin (bruising), small pinpoint bleeding spots, nail problems, acne, yeast infection, fungal infection, urinary tract infections, cystitis, blood test results showing altered liver function, increased blood fats 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 receiving anticoagulant therapy, eye bleeding.

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):

Lung infection caused by Pneumocystis jiroveci (pneumonia caused by Pneumocystis jiroveci).

Adverse effects with 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 mucosal reactions, which may include painful blisters and fever (Stevens-Johnson syndrome).

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

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: www.notificaRAM.es. By reporting adverse effects, you can help provide 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 expiry date stated on the vial label and the carton. The expiry date refers to 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 initial dilution of the concentrate with 1.8 ml of the supplied solvent, the mixture may be stored for up to 24 hours below 25°C and protected from light, prior to further dilution.

After subsequent dilution of the concentrate-solvent 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.

Medicines should not be disposed of via wastewater. Ask your pharmacist how to dispose of medicines and packaging you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Torisel

The active substance is temsirolimus.

Each concentrate vial contains 30 mg of temsirolimus.

After the first dilution of the concentrate with 1.8 ml of the solvent supplied, the concentration of temsirolimus is 10 mg/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 clear, colourless or pale yellow solution. The solvent is a clear or slightly opalescent, pale yellow or yellow solution. The solutions are practically free from visible particles.

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

Marketing Authorisation 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

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

Spain

Pfizer, S.L.
Tel: +34 91 490 99 00

Date of the most recent revision of this leaflet:

Other sources of information

Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. Links to other websites on rare diseases and orphan medicinal products are also available.

This information is intended for healthcare professionals only:

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

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

Bags and medical devices made of polyvinyl chloride (PVC) must not be used for the administration of preparations containing polysorbate 80, as polysorbate 80 may leach di-(2-ethylhexyl) phthalate (DEHP) from PVC.

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

Do not use if particles or colour changes are present. Use a new vial.

Dilution

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

Note: In mantle cell lymphoma, several vials are required for each dose above 25 mg. Each vial of Torisel must 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 9 mg/ml (0.9%) sodium chloride injection solution.

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

Do not use if particles or colour changes are present.

The preparation of the solution must be carried out aseptically in the following two-step process, in accordance with local standards for handling cytotoxic/cytostatic medicinal products:

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

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

One vial of Torisel concentrate contains 30 mg of temsirolimus: when 1.2 ml of concentrate is combined with 1.8 ml of the 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 up to 24 hours.

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

Withdraw the required volume of concentrate-solvent mixture (containing temsirolimus 10 mg/ml) from the vial; i.e., 2.5 ml for a temsirolimus dose of 25 mg.
Rapidly inject the withdrawn volume into 250 ml of 9 mg/ml (0.9%) sodium chloride injection solution to ensure adequate mixing.

The solution must be mixed by inverting the bag or bottle, avoiding excessive agitation, which may cause foaming.

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

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

Administration

The administration of the final diluted solution must be completed within 6 hours of the first addition of Torisel to the 9 mg/ml (0.9%) sodium chloride injection solution.
Torisel is administered by 30 to 60-minute infusion once weekly. The preferred method of administration is the use of an infusion pump to ensure accurate delivery of the medication.
Appropriate administration materials must be used to avoid excessive loss of the active substance and to reduce the rate of DEHP leaching. Administration materials must consist of DEHP- and PVC-free tubing with an appropriate filter. For administration, an in-line polysulfone filter with a pore size no greater than 5 microns is recommended to prevent infusion of particles larger than 5 microns. If the available administration set does not have an integrated in-line filter, a filter must be added at 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 to 5 microns may be used. The use of both an in-line filter and an end-filter is not recommended.
Torisel, after dilution, contains polysorbate 80 and therefore appropriate administration materials must be used. It is important to carefully follow the recommendations in sections 4.2 and 6.6 of the Summary of Product Characteristics.

Disposal

Disposal of unused medicinal product and all materials that have been in contact with it must be carried out in accordance with local regulations.