Torisel

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT  
 
Torisel 30 mg concentrate and solvent for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
Each vial of concentrate for solution for infusion contains 30 mg temsirolimus. 
 
After first dilution of the concentrate with 1.8 ml of solvent, the concentration of temsirolimus is 
10 mg/ml (see section 4.2). 
 
Excipient with known effect 
 
1 vial of concentrate contains 474 mg of anhydrous ethanol  
1.8 ml of the solvent provided contains 358 mg anhydrous ethanol 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM  
 
Concentrate and solvent for solution for infusion (sterile concentrate). 
 
The concentrate is a clear, colourless to light-yellow solution, free from visible particulates. 
 
The solvent is a clear to slightly turbid, light-yellow to yellow solution, free from visible particulates. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Renal cell carcinoma 
 
Torisel is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma 
(RCC) who have at least three of six prognostic risk factors (see section 5.1). 
 
Mantle cell lymphoma 
 
Torisel is indicated for the treatment of adult patients with relapsed and/or refractory mantle cell 
lymphoma (MCL) (see section 5.1). 
 
4.2 Posology and method of administration 
 
This medicinal product must be administered under the supervision of a physician experienced in the 
use of antineoplastic medicinal products. 
 
Posology 
 
Patients should be given intravenous diphenhydramine 25 mg to 50 mg (or similar antihistamine) 
approximately 30 minutes before the start of each dose of temsirolimus (see section 4.4). 
 
Treatment with Torisel should continue until the patient is no longer clinically benefiting from therapy 
or until unacceptable toxicity occurs. 



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Renal cell carcinoma 
The recommended dose of temsirolimus for advanced RCC is 25 mg administered by intravenous 
infusion over a 30- to 60-minute period once a week. 
 
Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction of 
temsirolimus therapy. If a suspected reaction is not manageable with dose delays, then temsirolimus 
may be reduced by 5 mg/week decrements. 
 
Mantle cell lymphoma 
The recommended dosing regimen of temsirolimus for MCL is 175 mg, infused over a 30-60 minute 
period once a week for 3 weeks followed by weekly doses of 75 mg, infused over a 30-60 minute 
period. The starting dose of 175 mg was associated with a significant incidence of adverse events and 
required dose reductions/delays in the majority of patients. The contribution of the initial 175 mg 
doses to the efficacy outcome is currently not known. 
 
Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction of 
temsirolimus therapy according to the guidelines in the following tables. If a suspected reaction is not 
manageable with dose delays and/or optimal medical therapy, then the dose of temsirolimus should be 
reduced according to the dose reduction table below. 
 

Dose reduction levels 

Dose reduction level 
Starting dose 

175 mg  
Continuing dosea 

75 mg 
-1 75 mg 50 mg 
-2 50 mg 25 mg 

a In the MCL clinical trial, up to two dose level reductions were allowed per patient. 
 

Temsirolimus dose modifications based on weekly ANC and platelet counts 
ANC Platelets Dose of temsirolimus 

1.0 x 109/l 50 x 109/l 100% of planned dose 

1.0 x 109/l 50 x 109/l Holda 
a Upon recovery to ANC 1.0 x 109/l (1000 cells/mm3) and platelets to 50 x 109/l 
(50,000 cells/mm3), the doses should be modified to the next lower dose level according to the table 
above. If the patient cannot maintain ANC 1.0 x 109/l and platelets 50 x 109/l on the new dose 
reduction level, then the next lower dose should be given once the counts have recovered. 
Abbreviation: ANC = absolute neutrophil count. 
 
Special populations 
 
Elderly  
No specific dose adjustment is necessary in elderly patients. 
 
Renal impairment 
No dose adjustment is recommended in patients with renal impairment. Temsirolimus should be used 
with caution in patients with severe renal impairment (see section 4.4). 
 
Hepatic impairment 
Temsirolimus should be used with caution in patients with hepatic impairment (see section 4.4). 
 
No dose adjustment is recommended for patients with advanced -RCC and mild to moderate hepatic 
impairment. For patients with RCC and severe hepatic impairment, the recommended dose for patients 
who have baseline platelets 100 x 109/l is 10 mg intravenous once a week infused over a 30-60 
minute period (see section 5.2). 



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No dose adjustment is recommended for patients with MCL and mild hepatic impairment. 
Temsirolimus should not be used in patients with MCL and moderate or severe hepatic impairment 
(see section 4.3). 
 
Paediatric population 
There is no relevant use of temsirolimus in the paediatric population for the indications of RCC and 
MCL. 
 
Temsirolimus should not be used in the paediatric population for the treatment of neuroblastoma, 
rhabdomyosarcoma or high-grade glioma, because of efficacy concerns based on the available data 
(see section 5.1). 
 
Method of administration 
 
Torisel is for intravenous use only. The diluted solution must be administered by intravenous infusion. 
 
The vial of concentrate must first be diluted with 1.8 ml of the supplied solvent to achieve a 
concentration of temsirolimus of 10 mg/ml. The required amount of the temsirolimus-solvent mixture 
(10 mg/ml) must be withdrawn and then rapidly injected into sodium chloride 9 mg/ml (0.9%) solution 
for injection. 
 
For instructions on dilution and preparation of the medicinal product before administration, see section 
6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80, or to any of the 
excipients listed in section 6.1. 
 
Use of temsirolimus in patients with MCL with moderate or severe hepatic impairment. 
 
4.4 Special warnings and precautions for use 
 
The incidence and severity of adverse events is dose-dependent. Patients receiving the starting dose of 
175 mg weekly for the treatment of MCL must be followed closely to decide on dose 
reductions/delays. 
 
Paediatric population 
 
Temsirolimus is not recommended for use in paediatric patients (see sections 4.2, 4.8 and 5.1). 
 
Elderly 
 
Based on the results of a Phase 3 study in RCC, elderly patients (65 years of age) may be more likely 
to experience certain adverse reactions, including oedema, diarrhoea, and pneumonia. Based on the 
results of a Phase 3 study in MCL, elderly patients (65 years of age) may be more likely to 
experience certain adverse reactions, including pleural effusion, anxiety, depression, insomnia, 
dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, taste loss, dizziness, upper respiratory 
infection, mucositis, and rhinitis. 
 



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Renal impairment/renal failure 
 
Temsirolimus elimination by the kidneys is negligible; studies in patients with varying renal 
impairment have not been conducted (see sections 4.2 and 5.2). Temsirolimus has not been studied in 
patients undergoing haemodialysis. 
 
Renal failure (including fatal outcomes) has been observed in patients receiving temsirolimus for 
advanced RCC and/or with pre-existing renal insufficiency (see section 4.8). 
 
Hepatic impairment 
 
Caution should be used when treating patients with hepatic impairment. 
 
Temsirolimus is cleared predominantly by the liver. In an open-label, dose-escalation Phase 1 study in 
110 subjects with advanced malignancies and either normal or impaired hepatic function, 
concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated 
aspartate aminotransferase (AST) or bilirubin levels. Assessment of AST and bilirubin levels is 
recommended before initiation of temsirolimus and periodically after. An increased rate of fatal events 
was observed in patients with moderate and severe hepatic impairment. The fatal events included those 
due to progression of disease; however a causal relationship cannot be excluded. 
 
Based on the Phase 1 study, no dose adjustment of temsirolimus is recommended for RCC patients 
with baseline platelet counts 100 x 109/l and mild to moderate hepatic impairment (total bilirubin up 
to 3 times upper limit of normal [ULN] with any abnormality of AST, or as defined by Child-Pugh 
Class A or B). For patients with RCC and severe hepatic impairment (total bilirubin >3 times ULN 
with any abnormality of AST, or as defined by Child-Pugh Class C), the recommended dose for 
patients who have baseline platelets 100 x 109/l is 10 mg intravenous once a week infused over a 
30-60 minute period (see section 4.2). 
 
Intracerebral bleeding 
 
Patients with central nervous system (CNS) tumours (primary CNS tumours or metastases) and/or 
receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding 
(including fatal outcomes) while receiving therapy with temsirolimus. 
 
Thrombocytopenia, neutropenia, and anaemia 
 
Grades 3 and 4 thrombocytopenia and/or neutropenia have been observed in the MCL clinical trial (see 
section 4.8). Patients on temsirolimus who develop thrombocytopenia may be at increased risk of 
bleeding events, including epistaxis (see section 4.8). Patients on temsirolimus with baseline 
neutropenia may be at risk of developing febrile neutropenia. Cases of anaemia have been reported in 
RCC and MCL (see section 4.8). Monitoring of complete blood count is recommended prior to 
initiating temsirolimus therapy and peridically thereafter. 
 
Infections 
 
Patients may be immunosuppressed and should be carefully observed for the occurrence of infections, 
including opportunistic infections. Among patients receiving 175 mg/week for the treatment of MCL, 
infections (including Grade 3 and 4 infections) were substantially increased compared to lower doses 
and compared to conventional chemotherapy. Cases of pneumocystis jiroveci pneumonia (PCP) some 
with fatal outcomes, have been reported in patients who received temsirolimus, many of whom also 
received corticosteroids or other immunosuppressive agents. Prophylaxis of PCP should be considered 
for patients who require concomitant use of corticosteroids or other immunosuppressive agents based 
upon current standard of care. 



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Cataracts 
 
Cataracts have been observed in some patients who received the combination of temsirolimus and 
interferon-α (IFN-α). 
 
Hypersensitivity/infusion reactions 
 
Hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), including 
and not limited to flushing, chest pain, dyspnoea, hypotension, apnoea, loss of consciousness, 
hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus (see 
section 4.8). These reactions can occur very early in the first infusion, but may also occur with 
subsequent infusions. Patients should be monitored early during the infusion and appropriate 
supportive care should be available. The temsirolimus infusion should be interrupted in all patients 
with severe infusion reactions and appropriate medical therapy administered. A benefit-risk 
assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or 
life-threatening reactions. 
 
If a patient develops a hypersensitivity reaction during the temsirolimus infusion despite the 
premedication, the infusion must be stopped and the patient observed for at least 30 to 60 minutes 
(depending on the severity of the reaction). At the discretion of the physician, treatment may be 
resumed after the administration of an H1-receptor antagonist (diphenhydramine or similar 
antihistamine) and a H2-receptor antagonist (intravenous famotidine 20 mg or intravenous ranitidine 
50 mg) approximately 30 minutes before restarting the temsirolimus infusion. Administration of 
corticosteroids may be considered; however, the efficacy of corticosteroid treatment in this setting has 
not been established. The infusion may then be resumed at a slower rate (up to 60 minutes) and should 
be completed within six hours from the time that temsirolimus is first added to sodium chloride 
9 mg/ml (0.9%) solution for injection. 
 
Because it is recommended that an H1 antihistamine be administered to patients before the start of the 
intravenous temsirolimus infusion, temsirolimus should be used with caution in patients with known 
hypersensitivity to the antihistamine or in patients who cannot receive the antihistamine for other 
medical reasons. 
 
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative 
dermatitis and hypersensitivity vasculitis, have been associated with the oral administration of 
sirolimus. 
 
Hyperglycaemia/glucose intolerance/diabetes mellitus 
 
Patients should be advised that treatment with temsirolimus may be associated with an increase in 
blood glucose levels in diabetic and non-diabetic patients. In the RCC clinical trial, a Phase 3 clinical 
trial for RCC, 26% of patients reported hyperglycaemia as an adverse event. In the MCL clinical trial, 
a Phase 3 clinical trial for MCL, 11% of patients reported hyperglycaemia as an adverse event. This 
may result in the need for an increase in the dose of, or initiation of, insulin and/or hypoglycaemic 
agent therapy. Patients should be advised to report excessive thirst or any increase in the volume or 
frequency of urination. 
 
Interstitial lung disease 
 
There have been cases of non-specific interstitial pneumonitis, including fatal reports, occurring in 
patients who received weekly intravenous temsirolimus. Some patients were asymptomatic or had 
minimal symptoms with pneumonitis detected on computed tomography scan or chest radiograph. 
Others presented with symptoms such as dyspnoea, cough, and fever. Some patients required 
discontinuation of temsirolimus or treatment with corticosteroids and/or antibiotics, while some 
patients continued treatment without additional intervention. It is recommended that patients undergo 
baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the 



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initiation of temsirolimus therapy. Periodical follow-up assessments may be considered. It is 
recommended that patients be followed closely for occurrence of clinical respiratory symptoms and 
patients should be advised to report promptly any new or worsening respiratory symptoms. If clinically 
significant respiratory symptoms develop, temsirolimus administration may be withheld until after 
recovery of symptoms and improvement of radiographic findings related to pneumonitis. 
Opportunistic infections such as PCP should be considered in the differential diagnosis. Empiric 
treatment with corticosteroids and/or antibiotics may be considered. For patients who require use of 
corticosteroids, prophylaxis of PCP should be considered based upon current standard of care. 
 
Hyperlipaemia 
 
The use of temsirolimus was associated with increases in serum triglycerides and cholesterol. In the 
RCC clinical trial 1, hyperlipaemia was reported as an adverse event in 27% of patients. In the MCL 
clinical trial, hyperlipaemia was reported as an adverse event in 9.3% of patients. This may require 
initiation, or increase, in the dose of lipid-lowering agents. Serum cholesterol and triglycerides should 
be tested before and during treatment with temsirolimus. The known association of temsirolimus with 
hyperlipaemia may predispose to myocardial infarction. 
 
Wound healing complications 
 
The use of temsirolimus has been associated with abnormal wound healing; therefore, caution should 
be exercised with the use of temsirolimus in the peri-surgical period. 
 
Malignancies 
 
The possible development of lymphoma and other malignancies, particularly of the skin, may result 
from immunosuppression. As usual for patients with increased risk for skin cancer, exposure to 
sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a 
sunscreen with a high protection factor. 
 
Concomitant use of temsirolimus with sunitinib 
 
The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting 
toxicities (Grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) were 
observed in 2 out of 3 patients treated in the first cohort of a Phase 1 study at doses of temsirolimus 
15 mg intravenous per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest) 
(see section 4.5). 
 
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or calcium channel blockers 
 
Caution should be exercised when temsirolimus is given concomitantly with ACE inhibitors (e.g. 
ramipril) and/or calcium channel blockers (e.g. amlodipine). An increased risk of angioneurotic 
oedema (including delayed reactions occurring two months following initiation of therapy) is possible 
in patients who receive temsirolimus concomitantly with an ACE inhibitor and/or a calcium channel 
blocker (see sections 4.5 and 4.8). 
 
Agents inducing CYP3A metabolism 
 
Agents such as carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s wort are strong 
inducers of CYP3A4/5 and may decrease composite exposure of the active drug substances, 
temsirolimus and its metabolite, sirolimus. Therefore, for patients with RCC, continuous 
administration beyond 5-7 days with agents that have CYP3A4/5 induction potential should be 
avoided. For patients with MCL, it is recommended that coadministration of CYP3A4/5 inducers 
should be avoided due to the higher dose of temsirolimus (see section 4.5). 
 



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Agents inhibiting CYP3A metabolism 
 
Agents such as protease inhibitors (nelfinavir, ritonavir), antifungals (e.g. itraconazole, ketoconazole, 
voriconazole), and nefazodone are strong CYP3A4 inhibitors and may increase blood concentrations 
of the active drug substances, temsirolimus and its metabolite, sirolimus. Therefore, concomitant 
treatment with agents that have strong CYP3A4 inhibition potential should be avoided. Concomitant 
treatment with moderate CYP3A4 inhibitors (e.g. aprepitant, erythromycin, fluconazole, verapamil, 
grapefruit juice) should only be administered with caution in patients receiving 25 mg and should be 
avoided in patients receiving temsirolimus doses higher than 25 mg (see section 4.5). Alternative 
treatments with agents that do not have CYP3A4 inhibition potential should be considered (see section 
4.5). 
 
Vaccinations 
 
Immunosuppressants may affect responses to vaccination. During treatment with temsirolimus, 
vaccination may be less effective. The use of live vaccines should be avoided during treatment with 
temsirolimus. Examples of live vaccines are: measles, mumps, rubella, oral polio, Bacillus Calmette-
Guérin (BCG), yellow fever, varicella, and TY21a typhoid vaccines. 
 
Excipients 
 
After first dilution of the concentrate with 1.8 ml of the supplied solvent, the concentrate-solvent 
mixture contains 35% volume ethanol (alcohol), i.e., up to 0.693 g per 25 mg dose of temsirolimus, 
equivalent to 17.6 ml beer or 7.3 ml wine per dose. Patients administered the higher dose of 175 mg of 
temsirolimus for the initial treatment of MCL may receive up to 4.85 g of ethanol (equivalent 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. The amount of alcohol in this medicinal product may impair the ability to 
drive or use machines (see section 4.7). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Concomitant use of temsirolimus with sunitinib 
 
The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting 
toxicities (Grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) were 
observed in 2 out of 3 patients treated in the first cohort of a Phase 1 study at doses of temsirolimus 
15 mg intravenous per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest) 
(see section 4.4). 
 
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or calcium channel blockers 
 
An increased incidence of angioneurotic oedema (including delayed reactions occurring two months 
following initiation of therapy) has been observed in patients who received temsirolimus or other 
mTOR inhibitors in combination with an ACE inhibitor (e.g. ramipril) and/or a calcium channel 
blocker (e.g. amlodipine) (see sections 4.4 and 4.8). 
 
Agents inducing CYP3A metabolism 
 
Co-administration of temsirolimus with rifampicin, a potent CYP3A4/5 inducer, had no significant 
effect on temsirolimus maximum concentration (Cmax) and area under the concentration vs. time curve 



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(AUC) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56%, 
compared to temsirolimus treatment alone. Therefore, concomitant treatment with agents that have 
CYP3A4/5 induction potential should be avoided (e.g. carbamazepine, phenobarbital, phenytoin, 
rifampicin, and St. John’s wort) (see section 4.4). 
 
Agents inhibiting CYP3A metabolism 
 
Co-administration of temsirolimus 5 mg with ketoconazole, a potent CYP3A4 inhibitor, had no 
significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and 
AUCsum (temsirolimus + sirolimus) increased 2.3-fold compared to temsirolimus alone. The effect on 
the unbound concentrations of sirolimus has not been determined, but is expected to be larger than the 
effect on whole-blood concentrations due to the saturable binding to red blood cells. The effect may 
also be more pronounced at a 25 mg dose. Therefore, substances that are potent inhibitors of 
CYP3A4 activity (e.g. nelfinavir, ritonavir, itraconazole, ketoconazole, voriconazole, nefazodone) 
increase sirolimus blood concentrations. Concomitant treatment of temsirolimus with these agents 
should be avoided (see section 4.4). 
 
Concomitant treatment with moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, clarithromycin, 
erythromycin, aprepitant, amiodarone) should only be administered with caution in patients receiving 
25 mg and should be avoided in patients receiving temsirolimus doses higher than 25 mg. 
 
Interaction with medicinal products metabolised by CYP2D6 or CYP3A4/5 
 
In 23 healthy subjects the concentration of desipramine, a CYP2D6 substrate, was unaffected when 
25 mg of temsirolimus was co-administered. In 36 patients with MCL, including 4 poor metabolisers, 
the effect of CYP2D6 inhibition after administration of single doses of 175 mg and 75 mg 
temsirolimus was investigated. Population PK analysis based on sparse sampling indicated no 
clinically significant interaction effect on AUC and Cmax of the CYP2D6 substrate desipramine. No 
clinically significant effect is anticipated when temsirolimus is co-administered with agents that are 
metabolised by CYP2D6. 
 
The effect of a 175 or 75 mg temsirolimus dose on CYP3A4/5 substrates has not been studied. 
However, in vitro studies in human liver microsomes followed by physiologically-based 
pharmacokinetic modelling indicate that the blood concentrations achieved after a 175 mg dose of 
temsirolimus most likely leads to relevant inhibition of CYP3A4/5 (see section 5.2). Therefore, 
caution is advised during concomitant administration of temsirolimus at a dose of 175 mg with 
medicinal products that are metabolised predominantly via CYP3A4/5 and that have a narrow 
therapeutic index. 
 
Interactions with medicinal products that are P-glycoprotein substrates 
 
In an in vitro study, temsirolimus inhibited the transport of P-glycoprotein (P-gp) substrates with an 
IC50 value of 2 µM. In vivo, the effect of P-gp inhibition has not been investigated in a clinical drug-
drug interaction study, however, recent preliminary data from a Phase 1 study of combined 
lenalidomide (dose of 25 mg) and temsirolimus (dose of 20 mg) seem to support the in vitro findings 
and suggest an increased risk of adverse events. Therefore, when temsirolimus is co-administered with 
medicinal products which are P-gp substrates (e.g. digoxin, vincristine, colchicine, dabigatran, 
lenalidomide, and paclitaxel) close monitoring for adverse events related to the co-administered 
medicinal products should be observed. 
 



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Amphiphilic agents 
 
Temsirolimus has been associated with phospholipidosis in rats. Phospholipidosis has not been 
observed in mice or monkeys treated with temsirolimus, nor has it been documented in patients treated 
with temsirolimus. Although phospholipidosis has not been shown to be a risk for patients 
administered temsirolimus, it is possible that combined administration of temsirolimus with other 
amphiphilic agents such as amiodarone or statins could result in an increased risk of amphiphilic 
pulmonary toxicity. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females 
 
Due to the unknown risk related to potential exposure during early pregnancy, women of childbearing 
potential must be advised not to become pregnant while using Torisel.  
 
Men with partners of childbearing potential should use medically acceptable contraception while 
receiving Torisel (see section 5.3). 
 
Pregnancy 
 
There are no adequate data from the use of temsirolimus in pregnant women. Studies in animals have 
shown reproductive toxicity. In reproduction studies in animals, temsirolimus caused 
embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated 
delays in skeletal ossification) in rats and rabbits. Teratogenic effects (omphalocele) were seen in 
rabbits (see section 5.3). 
 
The potential risk for humans is unknown. Torisel must not be used during pregnancy, unless the risk 
for the embryo is justified by the expected benefit for the mother. 
 
Breast-feeding 
 
It is unknown whether temsirolimus is excreted in human breast milk. The excretion of temsirolimus 
in milk has not been studied in animals. However, sirolimus, the main metabolite of temsirolimus, is 
excreted in milk of lactating rats. Because of the potential for adverse reactions in breast-fed infants 
from temsirolimus, breast-feeding should be discontinued during therapy. 
 
Fertility 
 
In male rats, decreased fertility and partly reversible reductions in sperm counts were reported (see 
section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Temsirolimus has no or negligible influence on the ability to drive and use machines based on the 
evidence available. 
 
For patients receiving the higher dose of 175 mg intravenous of temsirolimus for the treatment of 
MCL, the amount of ethanol in this medicinal product may impair the ability to drive or use machines 
(see section 4.4). 
 
4.8 Undesirable effects  
 
Summary of the safety profile 
 
The most serious reactions observed with temsirolimus in clinical trials are hypersensitivity/infusion 
reactions (including some life-threatening and rare fatal reactions), hyperglycaemia/glucose 



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intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracranial 
haemorrhage, renal failure, intestinal perforation, wound healing complication, thrombocytopenia, 
neutropenia (including febrile neutropenia), pulmonary embolism. 
 
The adverse reactions (all grades) experienced by at least 20% of the patients in RCC and MCL 
registration studies include anaemia, nausea, rash (including rash, pruritic rash, maculopapular rash, 
pustular rash), decreased appetite, oedema asthenia, fatigue, thrombocytopenia, diarrhoea, pyrexia, 
epistaxis, mucosal inflammation, stomatitis, vomiting, hyperglycaemia, hypercholesterolemia, 
dysgeusia, pruritus, cough, infection, pneumonia, dyspnoea. 
 
Cataracts have been observed in some patients who received the combination of temsirolimus and 
IFN-α. 
 
Based on the results of the phase 3 studies, elderly patients may be more likely to experience certain 
adverse reactions, including face oedema, pneumonia, pleural effusion, anxiety, depression, insomnia, 
dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, ageusia, dizziness, upper respiratory 
infection, mucositis, and rhinitis. 
 
Serious adverse reactions observed in clinical trials of temsirolimus for advanced RCC, but not in 
clinical trials of temsirolimus for MCL include: anaphylaxis, impaired wound healing, renal failure 
with fatal outcomes, and pulmonary embolism. 
 
Serious adverse reactions observed in clinical trials of temsirolimus for MCL, but not in clinical trials 
of temsirolimus for advanced RCC include: thrombocytopenia, and neutropenia (including febrile 
neutropenia). 
 
See section 4.4 for additional information concerning serious adverse reactions, including appropriate 
actions to be taken if specific reactions occur. 
 
The occurrence of undesirable effects following the dose of 175 mg temsirolimus/week for MCL, 
e.g. Grade 3 or 4 infections or thrombocytopenia, is associated with a higher incidence than that 
observed with either 75 mg temsirolimus/week or conventional chemotherapy. 
 
Tabulated list of adverse reactions 
 
Adverse reactions that were reported in RCC and MCL patients in the phase 3 studies are listed below 
(Table 1), by system organ class, frequency and grade of severity (NCI-CTCAE). Frequencies are 
defined as follows: very common (1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to 
<1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from 
the available data).Within each frequency grouping, adverse reactions are presented in order of 
decreasing seriousness. 
 



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Table 1: Adverse reactions from clinical trials in RCC (study 3066K1-304) and in MCL (study 
3066K1-305) 
 

System  
organ class 

Frequency Adverse reactions All grades 
n (%) 

Grade 
3 & 4 
n (%) 

Infections and 
infestations 

Very common 
 

Bacterial and viral infections 
(including infection, viral infection, 
cellulitis, herpes zoster, oral herpes, 
influenza, herpes simplex, herpes 
zoster ophthalmic, herpes virus 
infection, bacterial infection, 
bronchitis*, abscess, wound infection, 
post-operative wound infections) 

91 (28.3) 18 (5.6) 

Pneumoniaa (including interstitial 
pneumonia)

35 (10.9) 16 (5.0) 

Common 
 

Sepsis* (including septic shock) 5 (1.6) 5 (1.6) 
Candidiasis (including oral and anal 
candidiasis) and fungal 
infection/fungal skin infections 

16 (5.0) 0 (0.0) 

Urinary tract infection (including 
cystitis) 

29 (9.0) 6 (1.9) 

Upper respiratory tract infection 26 (8.1) 0 (0.0) 
Pharyngitis  6 (1.9) 0 (0.0) 
Sinusitis 10 (3.1) 0 (0.0) 
Rhinitis 7 (2.2) 0 (0.0) 
Folliculitis 4 (1.2) 0 (0.0) 

Uncommon  Laryngitis 1 (0.3) 0 (0.0) 
Blood and 
lymphatic system 
disorders 

Very common 
 

Neutropenia 46 (14.3) 30 (9.3) 
Thrombocytopenia** 97 (30.2) 56 (17.4)
Anaemia 132(41.1) 48 (15) 

Common 
 

Leukopenia ** 29 (9.0) 10 (3.1) 
Lymphopenia 25 (7.8) 16 (5.0) 

Immune system 
disorders 

Common Hypersensitivity reactions / drug 
hypersensitiviy 

24 (7.5) 1 (0.3) 

Metabolism and 
nutrition disorders 

Very common 
 

Hyperglycaemia 63 (19.6) 31 (9.7) 
Hypercholesterolaemia 60 (18.7) 1 (0.3) 
Hypertriglyceridaemia 56 (17.4) 8 (2.5) 
Decreased appetite 107 (33.3) 9 (2.8) 
Hypokalaemia 44 (13.7) 13 (4.0)

Common Diabetes mellitus 10 (3.1) 2 (0.6) 
Dehydration 17 (5.3) 8 (2.5)
Hypocalcaemia 21 (6.5) 5 (1.6) 
Hypophosphataemia 26 (8.1) 14 (4.4) 
Hyperlipidaemia 4 (1.2) 0 (0.0) 

Psychiatric 
disorders 

Very Common Insomnia 45 (14.0) 1 (0.3) 
Common 
 

Depression 16 (5.0) 0 (0.0)
Anxiety 28 (8.7) 0 (0.0) 



 13

System  
organ class 

Frequency Adverse reactions All grades 
n (%) 

Grade 
3 & 4 
n (%) 

Nervous system 
disorders 

Very common 
 

Dysgeusia 55 (17.1) 0 (0.0) 
Headache  55 (17.1) 2 (0.6) 

Common 
 

Dizziness 30 (9.3) 1 (0.3) 
Paresthaesia 21 (6.5) 1 (0.3) 
Somnolence 8 (2.5) 1 (0.3)
Ageusia 6 (1.9) 0 (0.0) 

Uncommon Intracranial haemorrhage  1 (0.3) 1 (0.3) 
Eye disorders 
 

Common Conjunctivitis (including 
conjunctivitis, lacrimal disorder)  

16 (5.0) 1 (0.3) 

Uncommon Eye haemorrhage*** 3 (0.9) 0 (0.0) 
Cardiac disorders Uncommon Pericardial effusion  3 (0.9) 1 (0.3) 
Vascular disorders Common 

 
 

Venous thromboembolism (including 
deep vein thrombosis, venous 
thrombosis) 

7 (2.2) 4 (1.2) 

Thrombophlebitis 4 (1.2) 0 (0.0) 
Hypertension 20 (6.2) 3 (0.9) 

Respiratory, 
thoracic and 
mediastinal 
disorders 

Very common 
 

Dyspnoeaa 79 (24.6) 27 (8.4) 
Epistaxis ** 69 (21.5) 1 (0.3) 
Cough 93 (29.0) 3 (0.9) 

Common 
 

Interstitial lung diseasea,**** 16 (5.0) 6 (1.9) 
Pleural effusiona,b 19 (5.9) 9 (2.8)

Uncommon Pulmonary embolism a 2 (0.6) 1 (0.3) 
Gastrointestinal 
disorders 

Very common 
 

Nausea 109 (34.0) 5 (1.6) 
Diarrhoea 109(34.0) 16 (5.0) 
Stomatitis 67 (20.9) 3 (0.9) 
Vomiting 57 (17.8) 4 (1.2)
Constipation 56 (17.4) 0 (0.0) 
Abdominal pain 56 (17.4) 10 (3.1) 

Common 
 
 

Gastrointestinal haemorrhage 
(including anal, rectal, haemorrhoidal, 
lip, and mouth haemorrhage, gingival 
bleeding)  

16 (5.0) 4 (1.2) 

Gastritis ** 7 (2.1) 2 (0.6) 
Dysphagia 13 (4.0) 0 (0.0) 
Abdominal distension  14 (4.4) 1 (0.3) 
Aphthous stomatitis 15 (4.7) 1 (0.3) 
Oral pain 9 (2.8) 1 (0.3) 
Gingivitis 6 (1.9) 0 (0.0) 

Uncommon Intestinala/duodenal perforation  2 ( 0.6) 1 (0.3) 



 14

System  
organ class 

Frequency Adverse reactions All grades 
n (%) 

Grade 
3 & 4 
n (%) 

Skin and 
subcutaneous 
tissue disorders 

Very common 
 

Rash (including rash, pruritic rash, 
maculo-papular rash, rash, generalised 
rash, macular rash, papular rash) 

138 (43.0) 16 (5.0) 

Pruritus (including pruritus 
generalised)

69 (21.5) 4 (1.2) 

Dry skin 32 (10.0) 1 (0.3) 
Common  Dermatitis 6 (1.9) 0 (0.0) 

Exfoliative rash 5 (1.6) 0 (0.0) 
Acne 15 (4.7) 0(0.0) 
Nail disorder 26 (8.1) 0 (0.0) 
Ecchymosis*** 5 (1.6) 0 (0.0) 
Petechiae*** 4 (1.2) 0 (0.0) 

Musculoskeletal 
and connective 
tissue disorders 

Very common 
 

Arthralgia 50 (15.6) 2 (0.6) 
Back pain 53 (16.5) 8 (2.5) 

Common Myalgia  19 ( 5.9) 0 (0.0) 
Renal and urinary 
disorders 

Common Renal failurea 5 (1.6) 0 (0.0) 

General disorders 
and administration 
site conditions 

Very common 
 

Fatigue 133 (41.4) 31 (9.7) 
Oedema (including generalised 
oedema, facial oedema, peripheral 
oedema, scrotal oedema, genital 
oedema) 

122 (38.0) 11 (3.4) 

Astheniaa 67 (20.9) 16 (5.0) 
Mucosal inflammation 66 (20.6) 7 (2.2) 
Pyrexia 91 (28.3) 5 (1.6) 
Pain 36 (11.2) 7 (2.2) 
Chills 32 (10.0) 1 (0.3) 
Chest pain 32 (10.0) 1 (0.3)

Uncommon Impaired wound healing 2 (0.6) 0 (0.0) 
Investigations Very common Blood creatinine increased 35 (10.9) 4 (1.2) 

Common Increased aspartate aminotransferase 27 (8.4) 5 (1.6) 
Common Increased alanine aminotransferase 17 (5.3) 2 (0.6) 

a: One fatal case 
b: One pleural effusion fatal event occurred in the low-dose (175/25 mg) arm of the MCL study 
*Most NCI-CTC Grade 3 and above reactions observed in clinical trials of temsirolimus for MCL 
** Most NCI-CTC all grades reactions observed in clinical trials of temsirolimus for MCL 
*** All NCI-CTC Grade 1 and 2 reactions observed in clinical trials of temsirolimus for MCL 
****Interstitial lung disease is defined by a cluster of related Preferred Terms: interstitial lung disease 
(n = 6), pneumonitisa (n = 7), alveolitis (n = 1), alveolitis allergic (n = 1), pulmonary fibrosis (n = 1) 
and eosinophilic pneumonia (n = 0). 
 



 15

Adverse reactions that were reported in post-marketing experience are listed below (Table 2). 
 
Table 2: Adverse reactions reported in post-marketing setting 
 
System Organ class Frequency Adverse reactions 
Infections and infestations Rare Pneumocystis jiroveci 

pneumonia 
Immune system disorders Not known Angioneurotic oedema-type 

reactions
Skin and subcutaneous tissue 
disorders 

Not known  Stevens-Johnson syndrome 

Musculoskeletal and 
connective tissue disorders 

Not known Rhabdomyolysis 

 
Description of selected adverse reactions 
 
Post-marketing experience 
Angioneurotic oedema-type reactions have been reported in some patients who received temsirolimus 
and ACE-inhibitors concomitantly. 
 
Cases of PCP, some with fatal outcomes, have been reported (see section 4.4). 

Paediatric population 
 
In a Phase 1/2 study, 71 patients (59 patients, aged from 1 to 17 years old, and 12 patients, aged 18 to 
21 years) were administered temsirolimus at doses ranging from 10 mg/m2 to 150 mg/m2 (see 
section 5.1). 
 
The adverse reactions reported by the highest percentage of patients were haematologic (anaemia, 
leukopenia, neutropenia, and thrombocytopenia), metabolic (hypercholesterolemia, hyperlipaemia, 
hyperglycaemia, increase of serum aspartate amino transferase (AST) and serum alanine 
aminotransferase (ALT) plasma levels), and digestive (mucositis, stomatitis, nausea, and vomiting). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no specific treatment for temsirolimus overdose. While temsirolimus has been safely 
administered to patients with renal cancer with repeated intravenous doses as high as 220 mg/m2, in 
MCL, two administrations of 330 mg temsirolimus/week in one patient resulted in Grade 3 rectal 
bleeding and Grade 2 diarrhoea. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors; ATC code: L01X E09 
 



 16

Mechanism of action 
 
Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds 
to an intracellular protein (FKBP-12), and the protein/temsirolimus complex binds and inhibits the 
activity of mTOR that controls cell division. In vitro, at high concentrations (10-20 M), temsirolimus 
can bind and inhibit mTOR in the absence of FKBP-12. Biphasic dose response of cell growth 
inhibition was observed. High concentrations resulted in complete cell growth inhibition in vitro, 
whereas inhibition mediated by FKBP-12/temsirolimus complex alone resulted in approximately 50% 
decrease in cell proliferation. Inhibition of mTOR activity results in a G1 growth delay at nanomolar 
concentrations and growth arrest at micromolar concentrations in treated tumour cells resulting from 
selective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc, and 
ornithine decarboxylase. When mTOR activity is inhibited, its ability to phosphorylate, and thereby 
control the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the 
P13 kinase/AKT pathway) that control cell division, is blocked. 
 
In addition to regulating cell cycle proteins, mTOR can regulate translation of the hypoxia-inducible 
factors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt to 
hypoxic microenvironments and to produce the angiogenic factor vascular endothelial growth factor 
(VEGF). The anti-tumour effect of temsirolimus, therefore, may also in part stem from its ability to 
depress levels of HIF and VEGF in the tumour or tumour microenvironment, thereby impairing vessel 
development. 
 
Clinical efficacy and safety 
 
Renal cell carcinoma 
 
The safety and efficacy of temsirolimus in the treatment of advanced RCC were studied in the 
following two randomised clinical trials: 
 
RCC clinical trial 1 
RCC clinical trial 1 was a Phase 3, multi-centre, 3-arm, randomised, open-label study in previously 
untreated patients with advanced RCC and with 3 or more of 6 pre-selected prognostic risk factors 
(less than 1 year from time of initial RCC diagnosis to randomisation, Karnofsky performance status 
of 60 or 70, haemoglobin less than the lower limit of normal, corrected calcium of greater than 
10 mg/dl, lactate dehydrogenase1.5 times the upper limit of normal, more than 1 metastatic organ 
site). The primary study endpoint was overall survival (OS). Secondary endpoints included 
progression-free survival (PFS), objective response rate (ORR), clinical benefit rate, time to treatment 
failure (TTF), and quality adjusted survival measurement. Patients were stratified for prior 
nephrectomy status within 3 geographic regions and were randomly assigned (1:1:1) to receive IFN-α 
alone (n = 207), temsirolimus alone (25 mg weekly; n = 209), or the combination of IFN-α and 
temsirolimus (n = 210). 
 
In RCC clinical trial 1, temsirolimus 25 mg was associated with a statistically significant advantage 
over IFN-α in the primary endpoint of OS at the 2nd pre-specified interim analysis (n = 446 events, 
p = 0.0078). The temsirolimus arm showed a 49% increase in median OS compared with the IFN-α 
arm. Temsirolimus also was associated with statistically significant advantages over IFN-α in the 
secondary endpoints of PFS, TTF, and clinical benefit rate. 
 
The combination of temsirolimus 15 mg and IFN-α did not result in a significant increase in overall 
survival when compared to IFN-α alone at either the interim analysis (median 8.4 vs. 7.3 months, 
hazard ratio = 0.96, p = 0.6965) or final analysis (median 8.4 vs. 7.3 months, hazard ratio = 0.93, 
p = 0.4902). Treatment with the combination of temsirolimus and IFN-α resulted in a statistically 
significant increase in the incidence of certain Grade 3-4 adverse events (weight loss, anaemia, 
neutropenia, thrombocytopenia and mucosal inflammation) when compared to the adverse events 
observed in the IFN-α or temsirolimus-alone arms. 



 17

 
Summary of efficacy results in temsirolimus RCC clinical trial 1  

Parameter  temsirolimus 
n = 209  

IFN-α  
n = 207  

P-value
a
 Hazard ratio 

(95% CI)
b

Pre-specified interim analysis  
Median overall survival, 
Months (95% CI)  10.9 (8.6, 12.7)  

7.3 (6.1, 
8.8) 0.0078  0.73 (0.58, 0.92) 

Final analysis  
Median overall survival, 
Months (95% CI)  10.9 (8.6, 12.7)  

7.3 (6.1, 
8.8)  0.0252  0.78 (0.63, 0.97) 

Median progression-free 
survival by independent 
assessment  
Months (95% CI)  

5.6 (3.9, 7.2)  3.2 (2.2, 4.0)  0.0042  0.74 (0.60, 0.91) 

Median progression-free 
survival by investigator 
assessment  
Months (95% CI)  

3.8 (3.6, 5.2)  1.9 (1.9, 2.2)  0.0028  0.74 (0.60, 0.90) 

Overall response rate by 
independent assessment  
% (95% CI)  

9.1 (5.2, 13.0)  5.3 (2.3, 8.4)  0.1361
c
 NA  

CI = confidence interval; NA = not applicable. 
a Based on log-rank test stratified by prior nephrectomy and region. 
b Based on Cox proportional hazard model stratified by prior nephrectomy and region (95% CI are 
descriptive only). 
c Based on Cochran-Mantel-Hansel test stratified by prior nephrectomy and region. 
 
In RCC clinical trial 1, 31% of patients treated with temsirolimus were 65 or older. In patients younger 
than 65, median overall survival was 12 months (95% CI 9.9, 14.2) with a hazard ratio of 
0.67 (95% CI 0.52, 0.87) compared with those treated with IFN-α. In patients 65 or older, median 
overall survival was 8.6 months (95% CI 6.4, 11.5) with a hazard ratio of 1.15 (95% CI 0.78, 1.68) 
compared with those treated with IFN-α. 
 
RCC clinical trial 2 
RCC clinical trial 2 was a randomised, double-blind, multi-centre, outpatient trial to evaluate the 
efficacy, safety, and pharmacokinetics of three dose levels of temsirolimus when administered to 
previously treated patients with advanced RCC. The primary efficacy endpoint was ORR, and OS was 
also evaluated. One hundred eleven (111) patients were randomly assigned in a 1:1:1 ratio to receive 
25 mg, 75 mg, or 250 mg intravenous temsirolimus weekly. In the 25 mg arm (n = 36), all patients had 
metastatic disease; 4 (11%) had no prior chemo- or immunotherapy; 17 (47%) had one prior treatment, 
and 15 (42%) had 2 or more prior treatments for RCC. Twenty-seven (27, 75%) had undergone a 
nephrectomy. Twenty-four (24, 67%) were Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) = 1, and 12 (33%) were ECOG PS = 0. 
 
For patients treated weekly with 25 mg temsirolimus OS was 13.8 months (95% CI: 9.0, 18.7 months); 
ORR was 5.6% (95% CI: 0.7, 18.7%). 
 
Mantle cell lymphoma 
 
The safety and efficacy of intravenous temsirolimus for the treatment of relapsed and/or refractory 
MCL were studied in the following Phase 3 clinical study. 
 



 18

MCL clinical trial 
MCL clinical trial is a controlled, randomised, open-label, multicentre, outpatient study comparing 
2 different dosing regimens of temsirolimus with an investigator's choice of therapy in patients with 
relapsed and/or refractory MCL. Subjects with MCL (that was confirmed by histology, 
immunophenotype, and cyclin D1 analysis) who had received 2 to 7 prior therapies that included 
anthracyclines and alkylating agents, and rituximab (and could include haematopoietic stem cell 
transplant) and whose disease was relapsed and/or refractory were eligible for the study. Subjects were 
randomly assigned in a 1:1:1 ratio to receive intravenous temsirolimus 175 mg (3 successive weekly 
doses) followed by 75 mg weekly (n = 54), intravenous temsirolimus 175 mg (3 successive weekly 
doses) followed by 25 mg weekly (n = 54), or the investigator’s choice of single-agent treatment (as 
specified in the protocol; n = 54). Investigator's choice therapies included: gemcitabine (intravenous: 
22 [41.5%]), fludarabine (intravenous: 12 [22.6%] or oral: 2 [3.8%]), chlorambucil (oral: 3 [5.7%]), 
cladribine (intravenous: 3 [5.7%]), etoposide (intravenous: 3 [5.7%]), cyclophosphamide (oral: 2 
[3.8%]), thalidomide (oral: 2 [3.8%]), vinblastine (intravenous: 2 [3.8%]), alemtuzumab (intravenous: 
1 [1.9%]), and lenalidomide (oral: 1 [1.9%]). The primary endpoint of the study was PFS, as assessed 
by an independent radiologist and oncology review. Secondary efficacy endpoints included OS and 
ORR. 
 
The results for the MCL clinical trial are summarised in the following table. Temsirolimus 
175/75 (temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly) led to an improvement 
in PFS compared with investigator's choice in patients with relapsed and/or refractory MCL that was 
statistically significant (hazard ratio = 0.44; p-value = 0.0009). Median PFS of the temsirolimus 
175/75 mg group (4.8 months) was prolonged by 2.9 months compared to the investigator's choice 
group (1.9 months). OS was similar. 
 
Temsirolimus also was associated with statistically significant advantages over investigator’s choice in 
the secondary endpoint of ORR. The evaluations of PFS and ORR were based on blinded independent 
radiologic assessment of tumour response using the International Workshop Criteria. 

Summary of efficacy results in temsirolimus MCL clinical trial 

Parameter 
 
 

temsirolimus 
175/75 mg 

n = 54 

Investigator’s 
choice 

(inv choice) 
n = 54 

P-value Hazard ratio (97.5% CI)a 

Median 
progression-free 
survivalb 
Months (97.5% CI) 

 
4.8 (3.1, 8.1) 

 
1.9 (1.6, 2.5) 

 
0.0009c 

 
0.44 (0.25, 0.78) 

Objective 
response rateb 
% (95% CI) 

22.2 (11.1, 33.3) 1.9 (0.0, 5.4) 0.0019d NA 

Overall survival 
Months (95% CI) 

 
12.8 (8.6, 22.3) 

 

 
10.3 (5.8, 15.8) 

 

 
0.2970c 

 

 
0.78 (0.49, 1.24) 

 
One-year survival 
rate 
% (97.5% CI) 

0.47 (0.31, 0.61) 0.46 (0.30, 0.60) 
  

a Compared with inv choice based on Cox proportional hazard model.  
b Disease assessment is based on radiographic review by independent radiologists and review of 
clinical data by independent oncologists. 
c Compared with inv choice based on log-rank test. 
d Compared with inv choice alone based on Fisher's exact test. 
Abbreviations: CI = confidence interval; NA = not applicable. 
 



 19

The temsirolimus 175 mg (3 successive weekly doses) followed by 25 mg weekly treatment arm did 
not result in a significant increase in PFS when compared with investigator’s choice (median 
3.4 vs. 1.9 months, hazard ratio = 0.65, CI = 0.39, 1.10, p = 0.0618). 
 
In the MCL clinical trial, there was no difference in efficacy in patients with respect to age, sex, race, 
geographic region, or baseline disease characteristics. 
 
Paediatric population 
 
In a Phase 1/2 safety and exploratory efficacy study, 71 patients (59 patients, aged from 1 to 17 years, 
and 12 patients, aged from 18 to 21 years) received temsirolimus as a 60-minute intravenous infusion 
once weekly in three-week cycles. In Part 1, 14 patients aged from 1 to 17 years with advanced 
recurrent/refractory solid tumours received temsirolimus at doses ranging from 10 mg/m2 to 
150 mg/m2. In Part 2, 45 patients aged from 1 to 17 years with recurrent/relapsed rhabdomyosarcoma, 
neuroblastoma, or high grade glioma were administered temsirolimus at a weekly dose of 75 mg/m2. 
Adverse events were generally similar to those observed in adults (see section 4.8). 
 
Temsirolimus was found to be ineffective in paediatric patients with neuroblastoma, 
rhabdomyosarcoma, and high-grade glioma (n = 52). For subjects with neuroblastoma, the objective 
response rate was 5.3% (95% CI: 0.1%, 26.0%). After 12 weeks of treatment, no response was 
observed in subjects with rhabdomyosarcoma or high-grade glioma. None of the 3 cohorts met the 
criterion for advancing to the second stage of the Simon 2-stage design. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Torisel in all subsets of the paediatric population in MCL (see section 4.2 on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following administration of a single 25 mg intravenous dose of temsirolimus in patients with cancer, 
mean Cmax in whole blood was 585 ng/ml (coefficient of variation [CV] = 14%), and mean AUC in 
blood was 1627 ng•h/ml (CV = 26%). For patients receiving 175 mg weekly for 3 weeks followed by 
75 mg weekly, estimated Cmax in whole blood at end of infusion was 2457 ng/ml during Week 1, and 
2574 ng/ml during Week 3. 
 
Distribution 
 
Temsirolimus exhibits a polyexponential decline in whole blood concentrations, and distribution is 
attributable to preferential binding to FKBP-12 in blood cells. The mean ±standard deviation (SD) 
dissociation constant (Kd) of binding was 5.1 ± 3.0 ng/ml, denoting the concentration at which 50% of 
binding sites in blood cells were occupied. Temsirolimus distribution is dose-dependent with mean 
(10th, 90th percentiles) maximal specific binding in blood cells of 1.4 mg (0.47 to 2.5 mg). Following 
a single 25 mg temsirolimus intravenous dose, mean steady-state volume of distribution in whole 
blood of patients with cancer was 172 liters. 
 
Biotransformation 
 
Sirolimus, an equally potent metabolite to temsirolimus, was observed as the principal metabolite in 
humans following intravenous treatment. During in vitro temsirolimus metabolism studies, sirolimus, 
seco-temsirolimus and seco-sirolimus were observed; additional metabolic pathways were 
hydroxylation, reduction and demethylation. Following a single 25 mg intravenous dose in patients 
with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer 
half-life of sirolimus. 
 



 20

Elimination 
 
Following a single 25 mg intravenous dose of temsirolimus, temsirolimus mean ± SD systemic 
clearance from whole blood was 11.4 ± 2.4 l/h. Mean half-lives of temsirolimus and sirolimus were 
17.7 hours and 73.3 hours, respectively. Following administration of [14C] temsirolimus, excretion was 
predominantly via the faeces (78%), with renal elimination of active substance and metabolites 
accounting for 4.6% of the administered dose. Sulfate or glucuronide conjugates were not detected in 
the human faecal samples, suggesting that sulfation and glucuronidation do not appear to be major 
pathways involved in the excretion of temsirolimus. Therefore, inhibitors of these metabolic pathways 
are not expected to affect the elimination of temsirolimus. 
 
Model-predicted values for clearance from plasma, after applying a 175 mg dose for 3 weeks, and 
subsequently 75 mg for 3 weeks, indicate temsirolimus and sirolimus metabolite trough concentrations 
of approximately 1.2 ng/ml and 10.7 ng/ml, respectively. 
 
Temsirolimus and sirolimus were demonstrated to be substrates for P-gp in vitro. 
 
Pharmacokinetic/pharmacodynamic relationship(s) 
 
Inhibition of CYP isoforms 
In in vitro studies in human liver microsomes, temsirolimus inhibited CYP3A4/5, CYP2D6, CYP2C9 
and CYP2C8 catalytic activity with Ki values of 3.1, 1.5, 14 and 27 μM, respectively. 
 
IC50 values for inhibition of CYP2B6 and CYP2E1 by temsirolimus were 48 and 100 μM, 
respectively. Based on a whole blood mean Cmax concentration of 2.6 μM for temsirolimus in MCL 
patients receiving the 175 mg dose there is a potential for interactions with concomitantly administered 
medicinal products that are substrates of CYP3A4/5 in patients treated with the 175 mg dose of 
temsirolimus (see section 4.5). Physiologically-based pharmacokinetic modelling has shown that after 
four weeks treatment with temsirolimus, the AUC of midazolam can be increased 3-to-4 fold and Cmax 
around 1.5-fold when midazolam is taken within a few hours after the start of the temsirolimus 
infusion. However, it is unlikely that whole blood concentrations of temsirolimus after intravenous 
administration of temsirolimus will inhibit the metabolic clearance of concomitant medicinal products 
that are substrates of CYP2C9, CYP2C8, CYP2B6 or CYP2E1. 
 
Special populations 
 
Hepatic impairment 
Temsirolimus should be used with caution when treating patients with hepatic impairment. 
 
Temsirolimus is cleared predominantly by the liver. 
 
Temsirolimus and sirolimus pharmacokinetics have been investigated in an open-label, dose-escalation 
study in 110 patients with advanced malignancies and either normal or impaired hepatic function. For 
7 patients with severe hepatic impairment (ODWG, group D) receiving the 10 mg dose of 
temsirolimus, the mean AUC of temsirolimus was ~1.7-fold higher compared to 7 patients with mild 
hepatic impairment (ODWG, group B). For patients with severe hepatic impairment, a reduction of the 
temsirolimus dose to 10 mg is recommended to provide temsirolimus plus sirolimus exposures in 
blood (mean AUCsum approximately 6510 ng·h/ml; n=7), which approximate to those following the 
25 mg dose (mean AUCsum approximately 6580 ng·h/ml; n=6) in patients with normal liver function 
(see sections 4.2 and 4.4). 
 
The AUCsum of temsirolimus and sirolimus on day 8 in patients with mild and moderate hepatic 
impairment receiving 25 mg temsirolimus was similar to that observed in patients without hepatic 
impairment receiving 75 mg (mean AUCsum mild: approximately 9770 ng*h/ml, n=13; moderate: 
approximately 12380 ng*h/ml, n=6; normal approximately 10580 ng*h/ml, n=4). 
 



 21

Gender, weight, race, age 
Temsirolimus and sirolimus pharmacokinetics are not significantly affected by gender. No relevant 
differences in exposure were apparent when data from the Caucasian population was compared with 
either the Japanese or Black population. 
 
In population pharmacokinetic-based data analysis, increased body weight (between 38.6 and 
158.9 kg) was associated with a two-fold range of trough concentration of sirolimus in whole blood. 
 
Pharmacokinetic data on temsirolimus and sirolimus are available in patients up to age 79 years. Age 
does not appear to affect temsirolimus and sirolimus pharmacokinetics significantly. 
 
Paediatric population 
In the paediatric population, clearance of temsirolimus was lower and exposure (AUC) was higher 
than in adults. In contrast, exposure to sirolimus was commensurately reduced in paediatric patients, 
such that the net exposure as measured by the sum of temsirolimus and sirolimus AUCs (AUCsum) was 
comparable to that for adults. 
 
5.3 Preclinical safety data 
 
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to or 
even lower than clinical exposure levels and with possible relevance to clinical use, were as follows: 
pancreatic islet cell vacuolation (rat), testicular tubular degeneration (mouse, rat and monkey), 
lymphoid atrophy (mouse, rat and monkey), mixed cell inflammation of the colon/caecum (monkey), 
and pulmonary phospholipidosis (rat). 
 
Diarrhoea with mixed cell inflammation of the caecum or colon was observed in monkeys and was 
associated with an inflammatory response, and may have been due to a disruption of the normal 
intestinal flora. 
 
General inflammatory responses, as indicated by increased fibrinogen and neutrophils, and/or changes 
in serum protein, were observed in mice, rats, and monkeys, although in some cases these clinical 
pathology changes were attributed to skin or intestinal inflammation as noted above. For some 
animals, there were no specific clinical observations or histological changes that suggested 
inflammation. 
 
Temsirolimus was not genotoxic in a battery of in vitro (bacterial reverse mutation in Salmonella 
typhimurium and Escherichia coli, forward mutation in mouse lymphoma cells, and chromosome 
aberrations in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays. 
 
Carcinogenicity studies have not been conducted with temsirolimus; however, sirolimus, the major 
metabolite of temsirolimus in humans, was carcinogenic in mice and rats. The following effects were 
reported in mice and/or rats in the carcinogenicity studies conducted: granulocytic leukaemia, 
lymphoma, hepatocellular adenoma and carcinoma, and testicular adenoma. 
 
Reductions in testicular weights and/or histological lesions (e.g., tubular atrophy and tubular giant 
cells) were observed in mice, rats, and monkeys. In rats, these changes were accompanied by a 
decreased weight of accessory sex organs (epididymides, prostate, seminal vesicles). In reproduction 
toxicity studies in animals, decreased fertility and partly reversible reductions in sperm counts were 
reported in male rats. Exposures in animals were lower than those seen in humans receiving clinically 
relevant doses of temsirolimus. 
 
 



 22

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Concentrate 
Anhydrous ethanol 
all-rac-α-Tocopherol (E 307) 
Propylene glycol 
Citric acid (E 330) 
 
Solvent 
Polysorbate 80 (E 433) 
Macrogol 400 
Anhydrous ethanol 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products, except those mentioned in 
section 6.6. 
 
Torisel 30 mg concentrate must not be added directly to aqueous infusion solutions. Direct addition of 
Torisel 30 mg concentrate to aqueous solutions will result in precipitation of medicinal product. 
 
Always dilute Torisel 30 mg concentrate with 1.8 ml of the supplied solvent before adding to the 
infusion solution. The concentrate-solvent mixture may only be administered in sodium chloride 
9 mg/ml (0.9%) solution for injection. 
 
Torisel, when diluted, contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl) 
phthalate extraction (DEHP) from polyvinyl chloride (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 be followed closely. 
 
PVC bags and medical devices must not be used for the administration of preparations containing 
polysorbate 80, because polysorbate 80 leaches DEHP from PVC. 
 
6.3 Shelf life 
 
Unopened vial 
3 years. 
 
After first dilution of Torisel 30 mg concentrate with 1.8 ml of the supplied solvent 
24 hours when stored below 25°C and protected from light. 
 
After further dilution of the concentrate-solvent mixture with sodium chloride 9 mg/ml (0.9%) solution 
for injection 
6 hours when stored below 25°C and protected from light. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C)  
 
Do not freeze. 
 
Keep the vials in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 



 23

 
6.5 Nature and contents of container 
 
Concentrate 
Clear glass vial (type 1), with butyl rubber stopper and a plastic flip-top closure sealed with aluminum 
containing 1.2 ml of concentrate 
 
Solvent 
Clear glass vial (type 1), with butyl rubber stopper and a plastic flip-top closure sealed with aluminum 
containing 2.2 ml of solvent 
 
Pack size: 1 vial of concentrate and 1 vial of solvent 
 
6.6 Special precautions for disposal and other handling 
 
During handling and preparation of admixtures, Torisel should be protected from excessive room light 
and sunlight. 
 
Torisel, when diluted, contains polysorbate 80 and therefore appropriate administration materials must 
be used (see sections 6.1 and 6.2). 
 
Bags/containers that come in contact with Torisel must be made of glass, polyolefin, or polyethylene. 
 
Torisel concentrate and solvent should be inspected visually for particulate matter and discolouration 
prior to administration. 
 
Do not use if particulates are present, or if discoloured. 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%) solution for injection. 
 
Note: For MCL, 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--solvent 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 (see section 4.2). 
 
The concentrate-solvent mixture should be inspected visually for particulate matter and discolouration. 
 
Do not use if particulates are present, or if discoloured. 
 
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 medicinal products: 
 
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 vial of Torisel 30 mg concentrate. 
 Mix the solvent 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 concentrate contains 30 mg of temsirolimus: when the 1.2 ml concentrate is 
combined with 1.8 ml of the supplied solvent, a total volume of 3.0 ml is obtained, and the 



 24

concentration of temsirolimus will be 10 mg/ml. The concentrate-solvent mixture is stable below 25°C 
for up to 24 hours. 
 
STEP 2:  ADMINISTRATION OF CONCENTRATE FOR SOLUTION FOR 

INFUSION-SOLVENT MIXTURE IN SODIUM CHLORIDE 9MG/ML (0.9%) 
SOLUTION FOR INJECTION  

 
 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%) 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 final diluted solution in the bag or bottle should be inspected visually for particulate matter and 
discolouration prior to administration. 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 MCL, 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 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 a week. 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 used 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 (see sections 6.1 and 6.2). 

 
• Torisel, when diluted, contains polysorbate 80,and therefore appropriate administration materials 

must be used (see sections 6.1 and 6.2). It is important that the recommendations in section 4.2 be 
followed closely. 

 
Disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER  
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 



 25

8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/424/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 November 2007 
 
Date of the latest renewal: 13 July 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency: http://www.ema.europa.eu 
 



 26

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
  

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



 27

 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Wyeth Lederle S.r.l. 
Via Franco Gorgone 
Zona Industriale 
95100 Catania 
Italy 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
 Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 



 28

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



 29

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 30

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Torisel 30 mg concentrate and solvent for solution for infusion 
temsirolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial of 1.2 ml of concentrate for solution for infusion contains 30 mg temsirolimus. 
 
After first dilution of the concentrate with 1.8 ml of the supplied solvent, the concentration of 
temsirolimus is 10 mg/ml. 
 
 
3. LIST OF EXCIPIENTS 
 
The concentrate also contains: anhydrous ethanol, all-rac-α-tocopherol (E 307), propylene glycol and  
citric acid (E 330). 
 
The solvent contains: polysorbate 80 (E 433), macrogol 400 and anhydrous ethanol. 
 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate and solvent for solution for infusion 
 
One vial of 1.2 ml concentrate. 
 
One vial of 2.2 ml solvent. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
To be diluted before use. 
Administration in infusion. 
 
Read the package leaflet before use and for dilution instructions. 
For intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 



 31

 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: handle with caution. 
 
 
8. EXPIRY DATE 
 
EXP 
 
Read the leaflet for the shelf life of the diluted product. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
Do not freeze. 
 
Keep the vials in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/424/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 



 32

15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA  
 
PC: 
SN: 
NN: 



 33

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
CONCENTRATE VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Torisel 30 mg sterile concentrate 
temsirolimus 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Dilute before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1.2 ml 
 
 
6. OTHER 
 
Cytotoxic 
 
Store in a refrigerator  
 
Do not freeze.  
 
Keep the vial in the outer carton.  
 



 34

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SOLVENT VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Solvent for Torisel 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
See package leaflet 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2.2 ml 
 
 
6. OTHER 
 
Contains: polysorbate 80 (E 433), macrogol 400, anhydrous ethanol. 
 



 35

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



 36

 
Package leaflet: Information for the patient 

 
Torisel 30 mg 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 get any side effects talk to your doctor, pharmacist or nurse. This includes any 

possibleside effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What Torisel is and what it is used for 
2. What you need to know before you receive Torisel 
3. How Torisel is given 
4. Possible side effects 
5. How to store Torisel 
6. 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) that 
blocks tumour cell growth and division. 
 
Torisel is used to treat the following types of cancer in adults: 
 
- Advanced cancer of the kidney (renal cancer). 
- Previously treated mantle cell lymphoma, a type of cancer affecting the lymph nodes. 
 
 
2. What you need to know before you receive Torisel 
 
Do not use Torisel: 
 
- if you are allergic to temsirolimus, to polysorbate 80 or to any of the other ingredients listed in 

section 6. 
- if you are allergic 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. 
 
Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before receiving 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 rare fatal allergic reactions. Discuss alternatives with your doctor. 

- if you have or have had tumours in your brain or spinal cord, bleeding problems or 
bruising, or if you are taking medicines which prevent your blood from clotting (such as 
warfarin and acenocoumarole). Torisel may lead to a higher risk of bleeding into your brain. 



 37

Tell your doctor if you are taking blood thinning medicines or have any bleeding or bruising 
while you are on Torisel. 

- if you have shortness of breath, cough, and/or fever. Torisel may weaken your immune 
system. You may be at risk of getting an infection of the blood, skin, upper respiratory tract 
(including pneumonia), and/or urinary tract while you are taking Torisel. Tell your doctor if 
you experience new or worsening symptoms, or if you are taking or have recently taken 
medicines that weaken your immune system. 

- if you have or have had inflammation of the lungs. Torisel may cause non-specific 
interstitial pneumonitis. Some patients did not have symptoms or had minimal symptoms. For 
this reason, your doctor may recommend a lung assessment by computed tomography scan or 
chest x-ray before and during your Torisel treatment. Promptly tell your doctor of any new or 
worsening respiratory symptoms such as shortness of breath or difficulty breathing. 

- if you drink alcohol or are an alcoholic. Torisel contains alcohol and can be harmful to those 
who drink alcohol or to those suffering from alcoholism. Tell your doctor if you have a 
drinking problem or consume alcohol (see 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. Tell your doctor if you develop any of the following 

signs and symptoms of liver problems during Torisel treatment: itching, yellow eyes or skin, 
dark urine, and pain or discomfort in the right upper stomach area. Your doctor will do blood 
tests to check your liver function and then may decide to lower the dose of Torisel. 

- if you have or have had high cholesterol levels. Torisel may elevate triglycerides and/or 
cholesterol, and this may require treatment with lipid-lowering agents (medicines used to 
reduce cholesterol in the blood). 

- if you are going to have surgery or if you had an operation recently. Torisel may increase 
the risk of problems with wound healing. You will usually be taken off Torisel if you are 
having an operation. Your doctor will decide when to start Torisel again. 

- if you are planning to have a vaccination during treatment with Torisel. A vaccination may 
be less effective or the use of certain vaccinations should be avoided during treatment with 
Torisel. 

- 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, runny nose, 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 agent therapy. Tell your doctor if you experience 
any excessive thirst or increased frequency and quantity of urination. 

- Torisel can decrease the number of blood cells that help in clotting and resisting infection. 
This may increase the risk of bleeding/bruising and infection (see section “Possible side 
effects"). 

- if you have or have had eye problems like cataracts. Your doctor may prescribe a visual 
examination before or during Torisel treatment. 

- if you are receiving Torisel, you may be at increased risk of cancers such as skin cancers and 
lymph node cancers (lymphoma). 

- if you are receiving Torisel, you may be at increased risk of heart attack. Tell your doctor if 
you experience symptoms such as pain or sensation of pressure in chest, arm, shoulders or jaw, 
shortness of breath, feeling sick (nausea), anxiety, sweating or dizziness. 

 
Talk to your doctor, pharmacist, nurse if you have any concern. 
 
Children and adolescents 
 
This medicine is not for children and adolescents below 18 years of age because advanced cancer of 
the kidney and mantle cell lymphoma are not relevant for these patients, and it did not work in other 
cancers. 
 



 38

Other medicines and Torisel 
 
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.  
Some medicines can interfere with the breakdown or metabolism of Torisel and therefore dose 
adjustment of Torisel may be required. In particular, you should 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 (including rifampicin) or antifungal medicines (including itraconazole, ketoconazole 

and voriconazole) 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 (such as enalapril, ramipril, lisinopril) or a 

calcium channel blocker (such as amlodipine) used to treat high blood pressure or other 
cardiovascular problems 

- amphiphilic medicines used to treat heart arrhythmias (such as amiodarone), or statins used to 
treat high cholesterol 

- sunitinib used to treat cancer of the kidney 
- medicines which are P-gp substrates (such as digoxin, vincristine, colchicine, dabigatran, 

lenalidomide, paclitaxel) 
 
Torisel with food and drink 
 
Grapefruit and grapefruit juice may increase blood concentrations of Torisel and should be avoided. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before receiving this medicine. 
 
Torisel has not been studied in pregnant women, and it must not be used during pregnancy, unless 
clearly necessary. 
 
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. 
 
Driving and using machines 
 
Torisel is unlikely to influence the ability to drive and use machines. However, feeling or being sick 
(nausea and vomiting) and difficulty in falling or staying asleep are very common side effects. If you 
feel sick (nausea and vomiting) or you have difficulty in falling or staying asleep, take special care 
when driving or using machines. 
 
For patients receiving the higher 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 below 
“Torisel contains ethanol [alcohol]”). 
 



 39

Torisel contains ethanol (alcohol) 
 
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. It is 
harmful if you are suffering from alcoholism, and it is 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 medicine may impair your ability to drive or alter the effects of other 
medicines (see sections “Warning and precautions” and “Driving and using machines”).  
 
 
3. How Torisel is given 
 
Torisel will always be prepared and given to you by a doctor or another healthcare professional as an 
intravenous infusion (into your vein). 
 
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. 
 
The Torisel concentrate must first be diluted 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%) 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 dose 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. 
 
Treatment with Torisel should continue until you are no longer benefiting from therapy or until 
unacceptable side effects occur. 
 
As this medicine is prepared and given by a healthcare professional, it is unlikely you will be given too 
much or that you will miss a dose. 
 
If you are concerned about this, tell your doctor immediately. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Side effects may be more pronounced with the higher dose of 175 mg per week during initial treatment 
for mantle cell lymphoma. 
 
The most important side effects you may experience during the treatment with Torisel are listed below. 
If you experience any of them, seek medical advice immediately. 
 
Allergic reactions 
You should tell your doctor or nurse immediately if you have symptoms of angioedema, such as 
swollen face, tongue or pharynx, and difficulty in breathing. 
 
If you experience any of these during the administration of Torisel, the doctor or nurse will stop the 
infusion. 



 40

 
Bleeding in the brain 
You should seek medical advice immediately if you feel confused, unusually tired, have difficulty in 
speaking or in swallowing and your pupils have different sizes. These symptoms might be caused by a 
bleeding in the brain. 
 
Intestinal puncture, tear or holes 
You should seek medical advice immediately if you have acute abdominal pain, high fever, nausea 
and vomiting, or blood in the stools. These symptoms might be caused by a perforation in your gut. 
 
Kidney failure 
You should seek medical advice immediately if you suffer from general swelling, shortness of 
breath, tiredness. These symptoms might be caused by a sudden decrease of kidney function. 
 
Embolism in the lung 
You should seek medical advice immediately if you experience shortness of breath, chest pain, 
coughing up blood, fast heartbeat, nausea, fainting, sweating, wheezing, and clammy or bluish skin. 
These symptoms might be caused by a blood clot in your lung. 
 
You should also tell your doctor straight away: 
- if you have cough, chest pain, difficulties in breathing. Your doctor may prescribe you an x-ray 

examination of your chest. 
- if the number of white cells in your blood has decreased. This may increase the risk of getting 

fever and infections. 
- if the number of platelet (a type of blood cell that helps to clot blood) has decreased. This may 

increase the risk of bleeding in your body. 
- if your blood levels of cholesterol and triglycerides have increased. 
- if you experience any excessive thirst or increased frequency and quantity of urination. Your 

doctor may prescribe you insulin and/or oral antidiabetic agent therapy. 
- if you have recently undertaken a surgery. Your doctor may delay the administration of Torisel 

until the wound is fully recovered as this medicine could interfere with the healing processes of 
pre-existing wounds. 

 
Other side effects with Torisel may include: 
 
Very common side 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), diarrhoea, constipation , 
headache, fever, sores and inflammation in the mouth and/or the digestive tract, cough, pneumonia, 
nose bleed, rash, itching, dry skin, decreased appetite, shortness of breath, low levels of potassium in 
the blood (which may cause muscle weakness), low red blood cell count, decreased number of a type 
of white blood cells which is associated with an increased risk of infection, high blood sugar, high 
cholesterol, high triglycerides abscess, infections ( including eye infection, flu, viral infections, 
bronchitis), abnormal kidney function (including kidney failure), blood tests that show changes in the 
way the kidney is working, change in the sense of taste, difficulty falling asleep, low number of 
platelets which may cause bleeding and bruising. 
 
Common side effects (may affect up to 1 in 10 people): 
 
Runny nose, gum redness and swelling, mouth pain (including sores inside the mouth), stomach 
bloating, sore throat, high blood pressure, pink eye including watery eye disorder, taste loss, redness 
and swelling of the follicles in the skin, allergic reactions, severe scaling of the skin, increased blood 
clotting (including thrombosis of the veins), low levels of calcium in the blood, low levels of 
phosphates in the blood, upper respiratory infections, inflammation of the lung, fluid in the chest 
cavity, infection in the blood, dehydration, agitation, depression, numbness and tingling of the skin, 
dizziness, sleepiness, bleeding (from the lips, mouth, stomach or intestines), inflammation of the lining 



 41

of the stomach, trouble with swallowing, skin bleeding (bruising), small pin-point haemorrage, nail 
disorder, acne, yeast infection, fungal infection, urinary tract infections, cystitis, blood tests that show 
changes in the way the liver is working, high blood fats other than triglycerides, diabetes, muscle pain. 
 
Uncommon side effects (may affect up to 1 in 100 people): 
 
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, eye bleeding. 
 
Embolism of the lung, perforation of the gut, problems with wound healing after surgery, 
inflammation and swelling of the voice box. 
 
Rare side effects (may affect up to 1 in 1,000 people): 
 
Lung infection caused by Pneumocystis jiroveci (Pneumocystis jiroveci pneumonia). 
 
Side effects for which frequency is not known (cannot be estimated from available data): 
 
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) 
 
Reporting of side effects 
If you get any side effect, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine 
 
 
5. How to store Torisel 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the vial label and carton. The expiry 
date refers to the last day of that month. 
 
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 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 further 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. 
 
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment. 
 



 42

 
6. Contents of the pack and other information 
 
What Torisel contains 
 
- The active substance is temsirolimus. 
 

Each vial of concentrate contains 30 mg of temsirolimus. 
 
After first dilution of the concentrate with 1.8 ml of the supplied solvent, the concentration of 
temsirolimus is 10 mg/ml. 

 
- The other ingredients in the concentrate are anhydrous ethanol, all-rac-α-tocopherol (E 307), 

propylene glycol and citric acid (E 330). The solvent contains polysorbate 80 (E 433), macrogol 
400 and anhydrous ethanol (see section “Torisel contains ethanol [alcohol]”). 

 
What Torisel looks like and contents of the pack 
 
Torisel is a concentrate and solvent for solution for infusion. 
The concentrate is a clear, colourless to light-yellow solution. The solvent is a clear to slightly turbid, 
light-yellow to yellow solution. The solutions are essentially free from visible particulates. 
 
Each pack of Torisel contains one glass vial of 1.2 ml of concentrate and one glass vial of 2.2 ml of 
solvent. 
 
Marketing Authorisation Holder 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturer 
Wyeth Lederle S.r.l. 
Via Franco Gorgone 
Zona Industriale 
95100 Catania 
Italy  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien  
Pfizer S.A./ N.V.  
Tél/Tel: +32 (0)2 554 62 11  
 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. +3705 2514000  
 

България  
Пфайзер Люксембург САРЛ, Клон България  
Тел.: +359 2 970 4333 
 

Luxembourg/Luxemburg  
Pfizer S.A./ N.V.  
Tél/Tel: +32 (0)2 554 62 11  
 

Česká republika  
Pfizer PFE, spol. s r.o. 
Tel: +420 283 004 111  
 

Magyarország  
Pfizer Kft.  
Tel.: +36 1 488 3700  
 

Danmark  
Pfizer ApS  
Tlf: +45 44 201 100  
 

Malta  
Vivian Corporation Ltd.  
Tel: +35621 344610 



 43

Deutschland  
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055-51000  
 

Nederland  
Pfizer bv 
Tel: +31 (0)10 406 43 01 
 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 
 

Norge  
Pfizer Norge AS  
Tlf: +47 67 52 61 00 
 

Ελλάδα  
PFIZER ΕΛΛΑΣ A.E. 
Tηλ: +30 210 67 85 800  
 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 

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

Polska  
Pfizer Polska Sp. z o.o.,  
Tel: +48 22 335 61 00  
 

France  
Pfizer 
Tél: +33 (0)1 58 07 34 40 
 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal 
Lda 
Tel: +351 21 423 5500 
 

Hrvatska 
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 
 

România 
Pfizer Romania S.R.L 
Tel: +40 (0) 21 207 28 00 

Ireland  
Pfizer Healthcare Ireland 
Tel: +1800 633 363 (toll free) 
Tel: +44 (0)1304 616161 
 

Slovenija 
Pfizer Luxembourg SARL, Pfizer, podružnica za 
svetovanje s področja farmacevtske dejavnosti, 
Ljubljana  
Tel: +386 (0)1 52 11 400 
 

Ísland  
Icepharma hf. 
Sími: +354 540 8000  

Slovenská republika 
Pfizer Luxembourg SARL, 
organizačná zložka 
Tel: +421 2 3355 5500   
 

Italia  
Pfizer S.r.l 
Tel: +39 06 33 18 21 
 

Suomi/Finland  
Pfizer Oy  
Puh/Tel: +358 (0)9 430 040 
 

Κύπρος  
PFIZER ΕΛΛΑΣ Α.Ε. (CYPRUS BRANCH)   
Tηλ: +357 22 817690  
 

Sverige  
Pfizer Innovations AB 
Tel: +46 (0)8 550 520 00 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel. +371 67035775 
 

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161 
 

 
This leaflet was last revised in <{MM/YYYY}> 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 



 44

__________________________________________________________________________________ 
 
The following information is intended for 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. 
 
Torisel concentrate and solvent should be inspected visually for particulate matter and discolouration 
prior to administration. 
 
Do not use if particulates are present, or if discoloured. 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%) 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-solvent 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. 
 
The concentrate-solvent mixture should be inspected visually for particulate matter and discolouration. 
Do not use if particulates are present, or if discoloured.  
 
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 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 vial of Torisel 30 mg concentrate. 
 Mix the solvent 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 concentrate contains 30 mg of temsirolimus: when the 1.2 ml concentrate is 
combined with 1.8 ml of the supplied solvent, a total volume of 3.0 ml is obtained and the 
concentration of temsirolimus will be 10 mg/ml. The concentrate- solvent mixture is stable below 
25°C for up to 24 hours. 
 
STEP 2: ADMINISTRATION OF CONCENTRATE FOR SOLUTION FOR INFUSION SOLVENT 

MIXTURE IN SODIUM CHLORIDE 9 MG/ML (0.9%) SOLUTION FOR INJECTION 
 

 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%) solution 
for injection to ensure adequate mixing. 

 



 45

The admixture should be mixed by inversion of the bag or bottle, avoiding excessive shaking, as this 
may cause foaming. 
 
The final diluted solution in the bag or bottle should be inspected visually for particulate matter and 
discolouration prior to administration. 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 a week. 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 used 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, and therefore appropriate administration materials 
must be used. It is important that the recommendations in sections 4.2 and 6.6 in the SmPC be 
followed closely. 

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

 

 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
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