TORISEL 30mg concentrate+solvent for solution for infusion medication leaflet

Torisel 30 mg concentrate and solvent for solution for infusion

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 is10 mg/ml (see section 4.2).

* 1 vial of concentrate contains 474 mg of anhydrous ethanol which is equivalent to394.6 mg/ml (39.46% w/v).

* 1.8 ml of the solvent provided contains 358 mg anhydrous ethanol which is equivalent to199.1 mg/ml (19.91% w/v).

* 1 vial of concentrate contains 604 mg of propylene glycol which is equivalent to 503.3 mg/ml(50.33% w/v).

For the full list of excipients, see section 6.1.

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.

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).

Torisel is indicated for the treatment of adult patients with relapsed and/or refractory mantle celllymphoma (MCL) (see section 5.1).

This medicinal product must be administered under the supervision of a physician experienced in theuse of antineoplastic medicinal products.

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 therapyor until unacceptable toxicity occurs.

The recommended dose of temsirolimus for advanced RCC is 25 mg administered by intravenousinfusion over a 30 to 60 minute period once a week.

Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction oftemsirolimus therapy. If a suspected reaction is not manageable with dose delays, then temsirolimusmay be reduced by 5 mg/week decrements.

The recommended dosing regimen of temsirolimus for MCL is 175 mg, infused over a 30 to 60 minuteperiod once a week for 3 weeks followed by weekly doses of 75 mg, infused over a 30 to 60 minuteperiod. The starting dose of 175 mg was associated with a significant incidence of adverse events andrequired dose reductions/delays in the majority of patients. The contribution of the initial 175 mgdoses to the efficacy outcome is currently not known.

Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction oftemsirolimus therapy according to the guidelines in the following tables. If a suspected reaction is notmanageable with dose delays and/or optimal medical therapy, then the dose of temsirolimus should bereduced according to the dose reduction table below.

Dose reduction levels

Starting dose Continuing dosea

Dose reduction level 175 mg 75 mg

- 1 75 mg 50 mg

- 2 50 mg 25 mga 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 Holdaa 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 thetable above. If the patient cannot maintain ANC 1.0 x 109/l and platelets 50 x 109/l on the newdose reduction level, then the next lower dose should be given once the counts have recovered.

Abbreviation: ANC = absolute neutrophil count.

No specific dose adjustment is necessary in elderly patients.

No dose adjustment is recommended in patients with renal impairment. Temsirolimus should be usedwith caution in patients with severe renal impairment (see section 4.4).

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 hepaticimpairment. For patients with RCC and severe hepatic impairment, the recommended dose for patientswho have baseline platelets 100 x 109/l is 10 mg intravenous once a week infused over a30 to 60 minute period (see section 5.2).

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).

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).

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 aconcentration 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%) solutionfor injection.

For instructions on dilution and preparation of the medicinal product before administration, see section6.6.

Hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80, or to any of theexcipients listed in section 6.1.

Use of temsirolimus in patients with MCL with moderate or severe hepatic impairment.

The incidence and severity of adverse events is dose-dependent. Patients receiving the starting dose of175 mg weekly for the treatment of MCL must be followed closely to decide on dosereductions/delays.

Temsirolimus is not recommended for use in paediatric patients (see sections 4.2, pct. 4.8 and 5.1).

Based on the results of a Phase 3 study in RCC, elderly patients (65 years of age) may be more likelyto experience certain adverse reactions, including oedema, diarrhoea, and pneumonia. Based on theresults of a Phase 3 study in MCL, elderly patients (65 years of age) may be more likely toexperience certain adverse reactions, including pleural effusion, anxiety, depression, insomnia,dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, taste loss, dizziness, upper respiratoryinfection, mucositis, and rhinitis.

Temsirolimus elimination by the kidneys is negligible; studies in patients with varying renalimpairment have not been conducted (see sections 4.2 and 5.2). Temsirolimus has not been studied inpatients undergoing haemodialysis.

Renal failure (including fatal outcomes) has been observed in patients receiving temsirolimus foradvanced RCC and/or with pre-existing renal insufficiency (see section 4.8).

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 in110 subjects with advanced malignancies and either normal or impaired hepatic function,concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevatedaspartate aminotransferase (AST) or bilirubin levels. Assessment of AST and bilirubin levels isrecommended before initiation of temsirolimus and periodically after. An increased rate of fatal eventswas observed in patients with moderate and severe hepatic impairment. The fatal events included thosedue 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 patientswith baseline platelet counts 100 x 109/l and mild to moderate hepatic impairment (total bilirubin upto 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 ULNwith any abnormality of AST, or as defined by Child-Pugh Class C), the recommended dose forpatients who have baseline platelets 100 x 109/l is 10 mg intravenous once a week infused over a30 to 60 minute period (see section 4.2).

Patients with central nervous system (CNS) tumours (primary CNS tumours or metastases) and/orreceiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding(including fatal outcomes) while receiving therapy with temsirolimus.

Grades 3 and 4 thrombocytopenia and/or neutropenia have been observed in the MCL clinical trial (seesection 4.8). Patients on temsirolimus who develop thrombocytopenia may be at increased risk ofbleeding events, including epistaxis (see section 4.8). Patients on temsirolimus with baselineneutropenia 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 toinitiating temsirolimus therapy and peridically thereafter.

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 dosesand compared to conventional chemotherapy. Cases of pneumocystis jiroveci pneumonia (PCP) somewith fatal outcomes, have been reported in patients who received temsirolimus, many of whom alsoreceived corticosteroids or other immunosuppressive agents. Prophylaxis of PCP should be consideredfor patients who require concomitant use of corticosteroids or other immunosuppressive agents basedupon current standard of care.

Cataracts have been observed in some patients who received the combination of temsirolimus andinterferon-α (IFN-α).

Hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), includingand not limited to flushing, chest pain, dyspnoea, hypotension, apnoea, loss of consciousness,hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus (seesection 4.8). These reactions can occur very early in the first infusion, but may also occur withsubsequent infusions. Patients should be monitored early during the infusion and appropriatesupportive care should be available. The temsirolimus infusion should be interrupted in all patientswith severe infusion reactions and appropriate medical therapy administered. A benefit-riskassessment should be done prior to the continuation of temsirolimus therapy in patients with severe orlife-threatening reactions.

If a patient develops a hypersensitivity reaction during the temsirolimus infusion despite thepremedication, 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 beresumed after the administration of an H1-receptor antagonist (diphenhydramine or similarantihistamine) and a H2-receptor antagonist (intravenous famotidine 20 mg or intravenous ranitidine50 mg) approximately 30 minutes before restarting the temsirolimus infusion. Administration ofcorticosteroids may be considered; however, the efficacy of corticosteroid treatment in this setting hasnot been established. The infusion may then be resumed at a slower rate (up to 60 minutes) and shouldbe completed within six hours from the time that temsirolimus is first added to sodium chloride9 mg/ml (0.9%) solution for injection.

Because it is recommended that an H1 antihistamine be administered to patients before the start of theintravenous temsirolimus infusion, temsirolimus should be used with caution in patients with knownhypersensitivity to the antihistamine or in patients who cannot receive the antihistamine for othermedical reasons.

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliativedermatitis and hypersensitivity vasculitis, have been associated with the oral administration ofsirolimus.

Patients should be advised that treatment with temsirolimus may be associated with an increase inblood glucose levels in diabetic and non-diabetic patients. In the RCC clinical trial, a Phase 3 clinicaltrial 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. Thismay result in the need for an increase in the dose of, or initiation of, insulin and/or hypoglycaemicagent therapy. Patients should be advised to report excessive thirst or any increase in the volume orfrequency of urination.

There have been cases of non-specific interstitial pneumonitis, including fatal reports, occurring inpatients who received weekly intravenous temsirolimus. Some patients were asymptomatic or hadminimal symptoms with pneumonitis detected on computed tomography scan or chest radiograph.

Others presented with symptoms such as dyspnoea, cough, and fever. Some patients requireddiscontinuation of temsirolimus or treatment with corticosteroids and/or antibiotics, while somepatients continued treatment without additional intervention. It is recommended that patients undergobaseline radiographic assessment by lung computed tomography scan or chest radiograph prior to theinitiation of temsirolimus therapy. Periodical follow-up assessments may be considered. It isrecommended that patients be followed closely for occurrence of clinical respiratory symptoms andpatients should be advised to report promptly any new or worsening respiratory symptoms. If clinicallysignificant respiratory symptoms develop, temsirolimus administration may be withheld until afterrecovery of symptoms and improvement of radiographic findings related to pneumonitis.

Opportunistic infections such as PCP should be considered in the differential diagnosis. Empirictreatment with corticosteroids and/or antibiotics may be considered. For patients who require use ofcorticosteroids, prophylaxis of PCP should be considered based upon current standard of care.

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 MCLclinical trial, hyperlipaemia was reported as an adverse event in 9.3% of patients. This may requireinitiation, or increase, in the dose of lipid-lowering agents. Serum cholesterol and triglycerides shouldbe tested before and during treatment with temsirolimus. The known association of temsirolimus withhyperlipaemia may predispose to myocardial infarction.

The use of temsirolimus has been associated with abnormal wound healing; therefore, caution shouldbe exercised with the use of temsirolimus in the peri-surgical period.

The possible development of lymphoma and other malignancies, particularly of the skin, may resultfrom immunosuppression. As usual for patients with increased risk for skin cancer, exposure tosunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using asunscreen with a high protection factor.

The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limitingtoxicities (Grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) wereobserved in 2 out of 3 patients treated in the first cohort of a Phase 1 study at doses of temsirolimus15 mg intravenous per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest)(see section 4.5).

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 angioneuroticoedema (including delayed reactions occurring two months following initiation of therapy) is possiblein patients who receive temsirolimus concomitantly with an ACE inhibitor and/or a calcium channelblocker (see sections 4.5 and 4.8).

Agents such as carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s wort are stronginducers of CYP3A4/5 and may decrease composite exposure of the active drug substances,temsirolimus and its metabolite, sirolimus. Therefore, for patients with RCC, continuousadministration beyond 5-7 days with agents that have CYP3A4/5 induction potential should beavoided. For patients with MCL, it is recommended that co-administration of CYP3A4/5 inducersshould be avoided due to the higher dose of temsirolimus (see section 4.5).

Agents such as protease inhibitors (nelfinavir, ritonavir), antifungals (e.g. itraconazole, ketoconazole,voriconazole), and nefazodone are strong CYP3A4 inhibitors and may increase blood concentrationsof the active drug substances, temsirolimus and its metabolite, sirolimus. Therefore, concomitanttreatment with agents that have strong CYP3A4 inhibition potential should be avoided. Concomitanttreatment 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 beavoided in patients receiving temsirolimus doses higher than 25 mg (see section 4.5). Alternativetreatments with agents that do not have CYP3A4 inhibition potential should be considered (see section4.5).

Concomitant use of mTOR inhibitors with inhibitors of P-glycoprotein (P-gp) may increase mTORinhibitor blood levels. Caution should be observed when co-administering temsirolimus with drugsthat inhibit P-glycoprotein. The clinical condition of the patient should be monitored closely. Doseadjustments of temsirolimus may be required (see section 4.5).

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 withtemsirolimus. Examples of live vaccines are: measles, mumps, rubella, oral polio, Bacillus

Calmette-Guérin (BCG), yellow fever, varicella, and TY21a typhoid vaccines.

After first dilution of the concentrate with 1.8 ml of the supplied solvent, the concentrate-solventmixture contains 35% volume ethanol (alcohol), i.e., up to 0.693 g per 25 mg dose of temsirolimus,equivalent to 18 ml beer or 7 ml wine per dose. Patients administered the higher dose of 175 mg oftemsirolimus for the initial treatment of MCL may receive up to 4.85 g of ethanol (equivalent to122 mlbeer or 49 ml wine per dose).

An example of ethanol exposure based on maximum single daily dose (see section 4.2) is as follows:

* Administration of the higher dose of 175 mg of temsirolimus for the initial treatment of MCLto an adult weighing 70 kg would result in exposure to 69.32 mg/kg of ethanol which maycause a rise in blood alcohol concentration (BAC) of about 11.5 mg/100 ml.

For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about50 mg/100 ml.

The amount of ethanol in this medicine is not likely to have an effect in adults and adolescents, and itseffects in children are not likely to be noticeable. It may have some effects, such as somnolence, inneonates and young children.

The ethanol content in this medicinal product should be carefully considered in the following patientgroups who may be at higher risk of ethanol-related adverse effects:

* Pregnant or breast-feeding women (see section 4.6)

* Patients suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups, such aspatients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter theeffects of other medicines.

Co-administration with medicines containing e.g. propylene glycol or ethanol may lead toaccumulation of ethanol and induce adverse effects, particularly in young children with low orimmature metabolic capacity.

The amount of alcohol in this medicinal product may impair the ability to drive or use machines (seesection 4.7).

Torisel contains propylene glycol (see section 2). An example of propylene glycol exposure based onmaximum single daily dose (see section 4.2) is as follows: Administration of the higher dose of175 mg of temsirolimus for the initial treatment of MCL to an adult weighing 70 kg would result in apropylene glycol exposure of 50.33 mg/kg/day.

Medical monitoring, including measurement of the osmolar and/or anion gap, is required in patientswith impaired renal and/or hepatic function who receive ≥50 mg/kg/day of propylene glycol. Variousadverse effects attributed to propylene glycol have been reported, such as renal dysfunction (acutetubular necrosis), acute renal failure and liver dysfunction.

Prolonged administration of propylene glycol-containing products, as well as co-administration withother substrates of alcohol dehydrogenase (e.g. ethanol), increase the risk of propylene glycolaccumulation and toxicity, especially in patients with liver or kidney impairment.

Propylene glycol doses of ≥1 mg/kg/day may induce serious adverse effects in neonates, while dosesof ≥50 mg/kg/day may induce adverse effects in children less than 5 years old and should only beadministered on a case by case basis.

Administration of ≥50 mg/kg/day of propylene glycol to pregnant or lactating women should only beconsidered on a case by case basis (see section 4.6).

Interaction studies have only been performed in adults.

The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limitingtoxicities (Grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) wereobserved in 2 out of 3 patients treated in the first cohort of a Phase 1 study at doses of temsirolimus15 mg intravenous per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest)(see section 4.4).

An increased incidence of angioneurotic oedema (including delayed reactions occurring two monthsfollowing initiation of therapy) has been observed in patients who received temsirolimus or othermTOR inhibitors in combination with an ACE inhibitor (e.g. ramipril) and/or a calcium channelblocker (e.g. amlodipine) (see sections 4.4 and 4.8).

Co-administration of temsirolimus with rifampicin, a potent CYP3A4/5 inducer, had no significanteffect on temsirolimus maximum concentration (Cmax) and area under the concentration vs. time curve(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).

Co-administration of temsirolimus 5 mg with ketoconazole, a potent CYP3A4 inhibitor, had nosignificant 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 onthe unbound concentrations of sirolimus has not been determined, but is expected to be larger than theeffect on whole-blood concentrations due to the saturable binding to red blood cells. The effect mayalso 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 agentsshould 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 receiving25 mg and should be avoided in patients receiving temsirolimus doses higher than 25 mg.

There have been reports of increased blood levels of other mTOR inhibitors during concomitant usewith cannabidiol. Co-administration of cannabidiol with another orally administered mTOR inhibitorin a healthy volunteer study led to an increase in exposure to the mTOR inhibitor of approximately2.5- fold for both Cmax and AUC, due to inhibition of intestinal P-gp efflux by cannabidiol.

Temsirolimus was demonstrated to be a substrate for P-gp in vitro. Caution should be used whencannabidiol and temsirolimus are co-administered, closely monitoring for side effects and adjusting thetemsirolimus dose as needed (see sections 4.2 and 4 4).

In 23 healthy subjects the concentration of desipramine, a CYP2D6 substrate, was unaffected when25 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 mgtemsirolimus was investigated. Population PK analysis based on sparse sampling indicated noclinically significant interaction effect on AUC and Cmax of the CYP2D6 substrate desipramine. Noclinically significant effect is anticipated when temsirolimus is co-administered with agents that aremetabolised 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-basedpharmacokinetic modelling indicate that the blood concentrations achieved after a 175 mg dose oftemsirolimus 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 withmedicinal products that are metabolised predominantly via CYP3A4/5 and that have a narrowtherapeutic index.

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 clinicaldrug-drug interaction study, however, recent preliminary data from a Phase 1 study of combinedlenalidomide (dose of 25 mg) and temsirolimus (dose of 20 mg) seem to support the in vitro findingsand suggest an increased risk of adverse events. Therefore, when temsirolimus is co-administered withmedicinal products which are P-gp substrates (e.g. digoxin, vincristine, colchicine, dabigatran,lenalidomide, and paclitaxel) close monitoring for adverse events related to the co-administeredmedicinal products should be observed.

Temsirolimus has been associated with phospholipidosis in rats. Phospholipidosis has not beenobserved in mice or monkeys treated with temsirolimus, nor has it been documented in patients treatedwith temsirolimus. Although phospholipidosis has not been shown to be a risk for patientsadministered temsirolimus, it is possible that combined administration of temsirolimus with otheramphiphilic agents such as amiodarone or statins could result in an increased risk of amphiphilicpulmonary toxicity.

Due to the unknown risk related to potential exposure during early pregnancy, women of childbearingpotential must be advised not to become pregnant while using Torisel.

Men with partners of childbearing potential should use medically acceptable contraception whilereceiving Torisel (see section 5.3).

There are no adequate data from the use of temsirolimus in pregnant women. Studies in animals haveshown reproductive toxicity. In reproduction studies in animals, temsirolimus causedembryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associateddelays in skeletal ossification) in rats and rabbits. Teratogenic effects (omphalocele) were seen inrabbits (see section 5.3).

The potential risk for humans is unknown. Torisel must not be used during pregnancy, unless the riskfor the embryo is justified by the expected benefit for the mother. The ethanol content of this productshould also be taken into account for pregnant women (see section 4.4).

Torisel contains propylene glycol (see section 4.4). Propylene glycol has not been shown to causereproductive or developmental toxicity in animals or humans, however, it may reach the foetus.

Administration of ≥50 mg/kg/day propylene glycol to pregnant women should only be considered on acase by case basis.

It is unknown whether temsirolimus is excreted in human breast milk. The excretion of temsirolimusin milk has not been studied in animals. However, sirolimus, the main metabolite of temsirolimus, isexcreted in milk of lactating rats. Because of the potential for adverse reactions in breast-fed infantsfrom temsirolimus, breast-feeding should be discontinued during therapy.

The ethanol content of this product should be taken into account in women who are breast-feeding (seesection 4.4).

Torisel contains propylene glycol (see section 4.4). Propylene glycol has not been shown to causereproductive or developmental toxicity in animals or humans, however, it has been found in milk andmay be orally absorbed by a nursing infant. Administration of ≥50 mg/kg/day propylene glycol tolactating women should only be considered on a case by case basis.

In male rats, decreased fertility and partly reversible reductions in sperm counts were reported (seesection 5.3).

Temsirolimus has no or negligible influence on the ability to drive and use machines based on theevidence 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).

The most serious reactions observed with temsirolimus in clinical trials are hypersensitivity/infusionreactions (including some life-threatening and rare fatal reactions), hyperglycaemia/glucoseintolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracranialhaemorrhage, 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 MCLregistration 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 certainadverse reactions, including face oedema, pneumonia, pleural effusion, anxiety, depression, insomnia,dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, ageusia, dizziness, upper respiratoryinfection, mucositis, and rhinitis.

Serious adverse reactions observed in clinical trials of temsirolimus for advanced RCC, but not inclinical trials of temsirolimus for MCL include: anaphylaxis, impaired wound healing, renal failurewith fatal outcomes, and pulmonary embolism.

Serious adverse reactions observed in clinical trials of temsirolimus for MCL, but not in clinical trialsof temsirolimus for advanced RCC include: thrombocytopenia, and neutropenia (including febrileneutropenia).

See section 4.4 for additional information concerning serious adverse reactions, including appropriateactions 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 thatobserved with either 75 mg temsirolimus/week or conventional chemotherapy.

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 aredefined 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 fromthe available data).Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1: Adverse reactions from clinical trials in RCC (study 3066K1-304) and in MCL (study3066K1-305)

System Frequency Adverse reactions All grades Gradeorgan class n (%) 3 & 4n (%)

Infections and Very common Bacterial and viral infections 91 (28.3) 18 (5.6)infestations (including infection, viral infection,cellulitis, herpes zoster, oral herpes,influenza, herpes simplex, herpeszoster ophthalmic, herpes virusinfection, bacterial infection,bronchitis*, abscess, wound infection,post-operative wound infections)

Pneumoniaa (including interstitial 35 (10.9) 16 (5.0)pneumonia)

Common Sepsis* (including septic shock) 5 (1.6) 5 (1.6)

Candidiasis (including oral and anal 16 (5.0) 0 (0.0)candidiasis) and fungalinfection/fungal skin infections

Urinary tract infection (including 29 (9.0) 6 (1.9)cystitis)

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 Very common Neutropenia 46 (14.3) 30 (9.3)lymphatic system Thrombocytopenia** 97 (30.2) 56 (17.4)disorders Anaemia 132(41.1) 48 (15)

Common Leukopenia ** 29 (9.0) 10 (3.1)

Lymphopenia 25 (7.8) 16 (5.0)

Immune system Common Hypersensitivity reactions/drug 24 (7.5) 1 (0.3)disorders hypersensitiviy

Metabolism and Very common Hyperglycaemia 63 (19.6) 31 (9.7)nutrition disorders 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 Very Common Insomnia 45 (14.0) 1 (0.3)disorders Common Depression 16 (5.0) 0 (0.0)

Anxiety 28 (8.7) 0 (0.0)

System Frequency Adverse reactions All grades Gradeorgan class n (%) 3 & 4n (%)

Nervous system Very common Dysgeusia 55 (17.1) 0 (0.0)disorders 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 16 (5.0) 1 (0.3)conjunctivitis, lacrimal disorder)

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 7 (2.2) 4 (1.2)deep vein thrombosis, venousthrombosis)

Thrombophlebitis 4 (1.2) 0 (0.0)

Hypertension 20 (6.2) 3 (0.9)

Respiratory, Very common Dyspnoeaa 79 (24.6) 27 (8.4)thoracic and Epistaxis ** 69 (21.5) 1 (0.3)mediastinal Cough 93 (29.0) 3 (0.9)disorders 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 Very common Nausea 109 (34.0) 5 (1.6)disorders 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 16 (5.0) 4 (1.2)(including anal, rectal, haemorrhoidal,lip, and mouth haemorrhage, gingivalbleeding)

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)

System Frequency Adverse reactions All grades Gradeorgan class n (%) 3 & 4n (%)

Skin and Very common Rash (including rash, pruritic rash, 138 (43.0) 16 (5.0)subcutaneous maculo-papular rash, rash, generalisedtissue disorders rash, macular rash, papular rash)

Pruritus (including pruritus 69 (21.5) 4 (1.2)generalised)

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 Very common Arthralgia 50 (15.6) 2 (0.6)and connective Back pain 53 (16.5) 8 (2.5)tissue disorders Common Myalgia 19 ( 5.9) 0 (0.0)

Renal and urinary Common Renal failurea 5 (1.6) 0 (0.0)disorders

General disorders Very common Fatigue 133 (41.4) 31 (9.7)and administration Oedema (including generalised 122 (38.0) 11 (3.4)site conditions oedema, facial oedema, peripheraloedema, scrotal oedema, genitaloedema)

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 caseb: 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).

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 jirovecipneumonia

Immune system disorders Not known Angioneurotic oedema-typereactions

Skin and subcutaneous tissue Not known Stevens-Johnson syndromedisorders

Musculoskeletal and Not known Rhabdomyolysisconnective tissue disorders

Angioneurotic oedema-type reactions have been reported in some patients who received temsirolimusand ACE-inhibitors concomitantly.

Cases of PCP, some with fatal outcomes, have been reported (see section 4.4).

In a Phase 1/2 study, 71 patients (59 patients, aged from 1 to 17 years old, and 12 patients, aged 18 to21 years) were administered temsirolimus at doses ranging from 10 mg/m2 to 150 mg/m2 (seesection 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 alanineaminotransferase (ALT) plasma levels), and digestive (mucositis, stomatitis, nausea, and vomiting).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for temsirolimus overdose. While temsirolimus has been safelyadministered 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 rectalbleeding and Grade 2 diarrhoea.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors; ATC code: L01E G01

Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus bindsto an intracellular protein (FKBP-12), and the protein/temsirolimus complex binds and inhibits theactivity of mTOR that controls cell division. In vitro, at high concentrations (10-20 M), temsirolimuscan bind and inhibit mTOR in the absence of FKBP-12. Biphasic dose response of cell growthinhibition 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 nanomolarconcentrations and growth arrest at micromolar concentrations in treated tumour cells resulting fromselective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc, andornithine decarboxylase. When mTOR activity is inhibited, its ability to phosphorylate, and therebycontrol 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-induciblefactors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt tohypoxic 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 todepress levels of HIF and VEGF in the tumour or tumour microenvironment, thereby impairing vesseldevelopment.

The safety and efficacy of temsirolimus in the treatment of advanced RCC were studied in thefollowing two randomised clinical trials:

RCC clinical trial 1 was a Phase 3, multi-centre, 3-arm, randomised, open-label study in previouslyuntreated 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 statusof 60 or 70, haemoglobin less than the lower limit of normal, corrected calcium of greater than10 mg/dl, lactate dehydrogenase1.5 times the upper limit of normal, more than 1 metastatic organsite). The primary study endpoint was overall survival (OS). Secondary endpoints includedprogression-free survival (PFS), objective response rate (ORR), clinical benefit rate, time to treatmentfailure (TTF), and quality adjusted survival measurement. Patients were stratified for priornephrectomy status within 3 geographic regions and were randomly assigned (1:1:1) to receive IFN-αalone (n = 207), temsirolimus alone (25 mg weekly; n = 209), or the combination of IFN-α andtemsirolimus (n = 210).

In RCC clinical trial 1, temsirolimus 25 mg was associated with a statistically significant advantageover 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-αarm. Temsirolimus also was associated with statistically significant advantages over IFN-α in thesecondary 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 overallsurvival 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 statisticallysignificant increase in the incidence of certain Grade 3-4 adverse events (weight loss, anaemia,neutropenia, thrombocytopenia and mucosal inflammation) when compared to the adverse eventsobserved in the IFN-α or temsirolimus-alone arms.

Summary of efficacy results in temsirolimus RCC clinical trial 1

Parameter temsirolimus IFN-α a

P-value Hazard ration = 209 n = 207 b(95% CI)

Pre-specified interim analysis

Median overall survival, 7.3 (6.1, 0.73 (0.58,10.9 (8.6, 12.7) 0.0078

Months (95% CI) 8.8) 0.92)

Final analysis

Median overall survival, 7.3 (6.1, 0.78 (0.63,10.9 (8.6, 12.7) 0.0252

Months (95% CI) 8.8) 0.97)

Median progression-freesurvival by independent 3.2 (2.2, 0.74 (0.60,5.6 (3.9, 7.2) 0.0042assessment 4.0) 0.91)

Months (95% CI)

Median progression-freesurvival by investigator 1.9 (1.9, 0.74 (0.60,3.8 (3.6, pct. 5.2) 0.0028assessment 2.2) 0.90)

Months (95% CI)

Overall response rate by5.3 (2.3, cindependent assessment 9.1 (5.2, 13.0) NA8.4) 0.1361% (95% CI)

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 aredescriptive 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 youngerthan 65, median overall survival was 12 months (95% CI 9.9, 14.2) with a hazard ratio of0.67 (95% CI 0.52, 0.87) compared with those treated with IFN-α. In patients 65 or older, medianoverall 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 was a randomised, double-blind, multi-centre, outpatient trial to evaluate theefficacy, safety, and pharmacokinetics of three dose levels of temsirolimus when administered topreviously treated patients with advanced RCC. The primary efficacy endpoint was ORR, and OS wasalso evaluated. One hundred eleven (111) patients were randomly assigned in a 1:1:1 ratio to receive25 mg, 75 mg, or 250 mg intravenous temsirolimus weekly. In the 25 mg arm (n = 36), all patients hadmetastatic 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 anephrectomy. 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%).

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.

MCL clinical trial is a controlled, randomised, open-label, multicentre, outpatient study comparing2 different dosing regimens of temsirolimus with an investigator's choice of therapy in patients withrelapsed 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 includedanthracyclines and alkylating agents, and rituximab (and could include haematopoietic stem celltransplant) and whose disease was relapsed and/or refractory were eligible for the study. Subjects wererandomly assigned in a 1:1:1 ratio to receive intravenous temsirolimus 175 mg (3 successive weeklydoses) followed by 75 mg weekly (n = 54), intravenous temsirolimus 175 mg (3 successive weeklydoses) followed by 25 mg weekly (n = 54), or the investigator’s choice of single-agent treatment (asspecified 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 assessedby 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. Temsirolimus175/75 (temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly) led to an improvementin PFS compared with investigator's choice in patients with relapsed and/or refractory MCL that wasstatistically significant (hazard ratio = 0.44; p-value = 0.0009). Median PFS of the temsirolimus175/75 mg group (4.8 months) was prolonged by 2.9 months compared to the investigator's choicegroup (1.9 months). OS was similar.

Temsirolimus also was associated with statistically significant advantages over investigator’s choice inthe secondary endpoint of ORR. The evaluations of PFS and ORR were based on blinded independentradiologic assessment of tumour response using the International Workshop Criteria.

Summary of efficacy results in temsirolimus MCL clinical trialtemsirolimus Investigator’s

Parameter 175/75 mg choice Hazard ratio

P-valuen = 54 (inv choice) (97.5% CI)an = 54

Medianprogression-free 4.8 (3.1, 8.1) 1.9 (1.6, 2.5) 0.0009c 0.44 (0.25, 0.78)survivalb

Months (97.5% CI)

Objectiveresponse rateb 22.2 (11.1, 33.3) 1.9 (0.0, 5.4) 0.0019d NA% (95% CI)

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 survivalrate0.47 (0.31, 0.61) 0.46 (0.30, 0.60)% (97.5% CI)a Compared with inv choice based on Cox proportional hazard model.b Disease assessment is based on radiographic review by independent radiologists and review ofclinical 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.

The temsirolimus 175 mg (3 successive weekly doses) followed by 25 mg weekly treatment arm didnot result in a significant increase in PFS when compared with investigator’s choice (median3.4 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.

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 infusiononce weekly in three-week cycles. In Part 1, 14 patients aged from 1 to 17 years with advancedrecurrent/refractory solid tumours received temsirolimus at doses ranging from 10 mg/m2 to150 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 objectiveresponse rate was 5.3% (95% CI: 0.1%, 26.0%). After 12 weeks of treatment, no response wasobserved in subjects with rhabdomyosarcoma or high-grade glioma. None of the 3 cohorts met thecriterion 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).

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 inblood was 1627 ng*h/ml (CV = 26%). For patients receiving 175 mg weekly for 3 weeks followed by75 mg weekly, estimated Cmax in whole blood at end of infusion was 2457 ng/ml during Week 1, and2574 ng/ml during Week 3.

Temsirolimus exhibits a polyexponential decline in whole blood concentrations, and distribution isattributable 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% ofbinding 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). Followinga single 25 mg temsirolimus intravenous dose, mean steady-state volume of distribution in wholeblood of patients with cancer was 172 liters.

Sirolimus, an equally potent metabolite to temsirolimus, was observed as the principal metabolite inhumans following intravenous treatment. During in vitro temsirolimus metabolism studies, sirolimus,seco-temsirolimus and seco-sirolimus were observed; additional metabolic pathways werehydroxylation, reduction and demethylation. Following a single 25 mg intravenous dose in patientswith cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longerhalf-life of sirolimus.

Following a single 25 mg intravenous dose of temsirolimus, temsirolimus mean ± SD systemicclearance from whole blood was 11.4 ± 2.4 l/h. Mean half-lives of temsirolimus and sirolimus were17.7 hours and 73.3 hours, respectively. Following administration of [14C] temsirolimus, excretion waspredominantly via the faeces (78%), with renal elimination of active substance and metabolitesaccounting for 4.6% of the administered dose. Sulfate or glucuronide conjugates were not detected inthe human faecal samples, suggesting that sulfation and glucuronidation do not appear to be majorpathways involved in the excretion of temsirolimus. Therefore, inhibitors of these metabolic pathwaysare not expected to affect the elimination of temsirolimus.

Model-predicted values for clearance from plasma, after applying a 175 mg dose for 3 weeks, andsubsequently 75 mg for 3 weeks, indicate temsirolimus and sirolimus metabolite trough concentrationsof approximately 1.2 ng/ml and 10.7 ng/ml, respectively.

Temsirolimus and sirolimus were demonstrated to be substrates for P-gp in vitro.

In in vitro studies in human liver microsomes, temsirolimus inhibited CYP3A4/5, CYP2D6, CYP2C9and 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 MCLpatients receiving the 175 mg dose there is a potential for interactions with concomitantly administeredmedicinal products that are substrates of CYP3A4/5 in patients treated with the 175 mg dose oftemsirolimus (see section 4.5). Physiologically-based pharmacokinetic modelling has shown that afterfour weeks treatment with temsirolimus, the AUC of midazolam can be increased 3-to-4 fold and Cmaxaround 1.5-fold when midazolam is taken within a few hours after the start of the temsirolimusinfusion. However, it is unlikely that whole blood concentrations of temsirolimus after intravenousadministration of temsirolimus will inhibit the metabolic clearance of concomitant medicinal productsthat are substrates of CYP2C9, CYP2C8, CYP2B6 or CYP2E1.

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-escalationstudy in 110 patients with advanced malignancies and either normal or impaired hepatic function. For7 patients with severe hepatic impairment (ODWG, group D) receiving the 10 mg dose oftemsirolimus, the mean AUC of temsirolimus was ~1.7-fold higher compared to 7 patients with mildhepatic impairment (ODWG, group B). For patients with severe hepatic impairment, a reduction of thetemsirolimus dose to 10 mg is recommended to provide temsirolimus plus sirolimus exposures inblood (mean AUCsum approximately 6510 ng·h/ml; n=7), which approximate to those following the25 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 hepaticimpairment receiving 25 mg temsirolimus was similar to that observed in patients without hepaticimpairment 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).

Temsirolimus and sirolimus pharmacokinetics are not significantly affected by gender. No relevantdifferences in exposure were apparent when data from the Caucasian population was compared witheither the Japanese or Black population.

In population pharmacokinetic-based data analysis, increased body weight (between 38.6 and158.9 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. Agedoes not appear to affect temsirolimus and sirolimus pharmacokinetics significantly.

In the paediatric population, clearance of temsirolimus was lower and exposure (AUC) was higherthan 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) wascomparable to that for adults.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to oreven 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 wasassociated with an inflammatory response, and may have been due to a disruption of the normalintestinal flora.

General inflammatory responses, as indicated by increased fibrinogen and neutrophils, and/or changesin serum protein, were observed in mice, rats, and monkeys, although in some cases these clinicalpathology changes were attributed to skin or intestinal inflammation as noted above. For someanimals, there were no specific clinical observations or histological changes that suggestedinflammation.

Temsirolimus was not genotoxic in a battery of in vitro (bacterial reverse mutation in Salmonellatyphimurium and Escherichia coli, forward mutation in mouse lymphoma cells, and chromosomeaberrations in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.

Carcinogenicity studies have not been conducted with temsirolimus; however, sirolimus, the majormetabolite of temsirolimus in humans, was carcinogenic in mice and rats. The following effects werereported 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 giantcells) were observed in mice, rats, and monkeys. In rats, these changes were accompanied by adecreased weight of accessory sex organs (epididymides, prostate, seminal vesicles). In reproductiontoxicity studies in animals, decreased fertility and partly reversible reductions in sperm counts werereported in male rats. Exposures in animals were lower than those seen in humans receiving clinicallyrelevant doses of temsirolimus.

Anhydrous ethanolall-rac-α-Tocopherol (E 307)

Propylene glycol (E 1520)

Citric acid (E 330)

Polysorbate 80 (E 433)

Macrogol 400

Anhydrous ethanol

This medicinal product must not be mixed with other medicinal products, except those mentioned insection 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 theinfusion solution. The concentrate-solvent mixture may only be administered in sodium chloride9 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 consideredduring the preparation and administration of Torisel. It is important that the recommendations insections 4.2 and 6.6 be followed closely.

PVC bags and medical devices must not be used for the administration of preparations containingpolysorbate 80, because polysorbate 80 leaches DEHP from PVC.

Unopened vial4 years.

After first dilution of Torisel 30 mg concentrate with 1.8 ml of the supplied solvent24 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%) solutionfor injection6 hours when stored below 25°C and protected from light.

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.

Clear glass vial (type 1), with butyl rubber stopper and a plastic flip-top closure sealed with aluminumcontaining 1.2 ml of concentrate

Clear glass vial (type 1), with butyl rubber stopper and a plastic flip-top closure sealed with aluminumcontaining 2.2 ml of solvent

Pack size: 1 vial of concentrate and 1 vial of solvent

During handling and preparation of admixtures, Torisel should be protected from excessive room lightand sunlight.

Torisel, when diluted, contains polysorbate 80 and therefore appropriate administration materials mustbe 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 discolourationprior to administration.

Do not use if particulates are present, or if discoloured. Use a new vial.

The concentrate for solution for infusion must be diluted with the supplied solvent beforeadministration 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 bediluted according to the instructions below. The required amount of concentrate-solvent mixture fromeach 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 manneraccording 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 beallowed for air bubbles to subside. The solution should be a clear to slightly turbid, colourlessto 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 iscombined with 1.8 ml of the supplied solvent, a total volume of 3.0 ml is obtained, and theconcentration 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 temsirolimus10 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%) solutionfor injection to ensure adequate mixing.

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

The final diluted solution in the bag or bottle should be inspected visually for particulate matter anddiscolouration 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 of the final diluted solution should be completed within six hours from the timethat 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 thepreferred method of administration to ensure accurate delivery of the medicinal product.

* Appropriate administration materials must be used to avoid excessive loss of medicinal productand to decrease the rate of DEHP extraction. The administration materials must consist ofnon-DEHP, non-PVC tubing with appropriate filter. An in-line polyethersulfone filter with a poresize of not greater than 5 microns is recommended for administration to avoid the possibility ofparticles bigger than 5 microns being infused. If the administration set available does not have anin-line filter incorporated, a filter should be added at the end of the set (i.e., an end-filter) beforethe admixture reaches the vein of the patient. Different end-filters can be used ranging in filterpore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is notrecommended (see sections 6.1 and 6.2).

* Torisel, when diluted, contains polysorbate 80,and therefore appropriate administration materialsmust be used (see sections 6.1 and 6.2). It is important that the recommendations in section 4.2 befollowed closely.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/07/424/001

Date of first authorisation: 19 November 2007

Date of the latest renewal: 13 July 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu