TORISEL 25 mg/ml concentrate and diluent for solution for infusion.

1 vial TORISEL 25 mg/ml concentrate contains:

30 mg temsirolimus dissolved in a total volume of 1.2 ml

Therefore, 1 ml of TORISEL concentrate contains 25 mg temsirolimus.

After dilution of TORISEL 25 mg/ml concentrate with 1.8 ml of withdrawn diluent, the concentration of temsirolimus is 10 mg/ml.

Excipients :

1 vial TORISEL 25 mg/ml concentrate contains 474 mg anhydrous ethanol.

1 vial of the diluent, provided contains 358 mg anhydrous ethanol.

For a full list of excipients, see section 6.1.

Concentrate and diluent for solution for infusion.

The concentrate is a clear, colourless to light-yellow solution, essentially free from visible particulates.

The diluent is a clear to slightly turbid, light-yellow to yellow solution, essentially free from visible particulates.

Renal cell carcinoma

TORISEL is indicated for the first-line treatment of 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).

TORISEL must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.

The total volume (1.2 ml) of 1 vial TORISEL 25 mg/ml concentrate must be diluted with 1.8 ml of withdrawn diluent to achieve a concentration of temsirolimus of 10 mg/ml. Withdraw the required amount of the temsirolimus 10 mg/ml mixture and then inject rapidly into sodium chloride 9 mg/ml (0.9%) solution for injection.

For instructions on preparation, see section 6.6.

Patients should be given intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus.

Treatment with TORISEL should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. No special dose modification is required for any of the populations that have been studied (gender, elderly).

Renal cell carcinoma

The recommended dose of temsirolimus for advanced renal cell carcinoma administered intravenously is 25 mg infused over a 30 to 60minute period once weekly (see section 6.6 for instructions on dilution, administration and disposal).

Management 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 mantle cell lymphoma is 175 mg, infused over a 30-60 minute period once weekly 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.

Management 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

Temsirolimus Dose Modifications Based on Weekly ANC and Platelet Counts

Paediatric patients

Experience in paediatric patients is limited. The safety and effectiveness in paediatric patients have not been established. Therefore, the use of TORISEL in the paediatric population is not recommended until further information on effectiveness and safety is available.

Elderly patients

No specific dose adjustment is necessary.

Renal impairment

No dose adjustment of temsirolimus 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 of temsirolimus is recommended for patients with advanced renal cell carcinoma (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 IV once a week infused over a 30-60 minute period (see section 5.2).

Hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80, or to any of the excipients of TORISEL.

Use of temsirolimus in patients with mantle cell lymphoma with moderate or severe hepatic impairment is not recommended (see section 4.4).

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 patients

Temsirolimus is not recommended for use in paediatric patients due to insufficient data on safety.

Elderly patients

Based on the results of a phase 3 study in renal cell carcinoma, 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 mantle cell lymphoma, elderly patients ( 65 years of age) may be more likely to experience certain adverse reactions, including pleural effusion, anxiety, depression, insomnia, dyspnoea, leukopaenia, lymphopaenia, myalgia, arthralgia, taste loss, dizziness, upper respiratory infection, mucositis, and rhinitis.

Renal impairment

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). TORISEL has not been studied in patients undergoing haemodialysis.

Renal failure

Renal failure (including fatal outcomes) has been observed in patients receiving TORISEL for advanced renal cell cancer and/or with pre-existing renal insufficiency (see section 4.8).

Hepatic impairment

Temsirolimus is cleared predominantly by the liver. Based on an open-label, dose-escalation study in 112 subjects with advanced malignancies and either normal or impaired hepatic function, no dose adjustment of temsirolimus is recommended for patients with baseline platelet counts 100x10⁹/l and advanced renal cell carcinoma (RCC) 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 IV 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.

Thrombocytopaenia and neutropaenia

Grades 3 and 4 thrombocytopaenia and/or neutropaenia have been observed in the MCL Clinical Trial (see section 4.8). Patients on temsirolimus who develop thrombocytopaenia may be at increased risk of bleeding events, including epistaxis (see section 4.8). Patients on temsirolimus with baseline neutropaenia may be at risk of developing febrile neutropaenia.

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.

Cataracts

Cataracts have been observed in some patients who received the combination of temsirolimus and interferon-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. 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 TORISEL 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 TORISEL 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 TORISEL 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 TORISEL 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 renal cell carcinoma, 26% of patients reported hyperglycaemia as an adverse event. In the MCL Clinical Trial, a phase 3 clinical trial for mantle cell lymphoma, 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 rare fatal reports, occurring in patients who received weekly intravenous TORISEL. Some patients were asymptomatic 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 TORISEL or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be followed for clinical respiratory symptoms.

Hyperlipaemia

The use of TORISEL 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 TORISEL.

Wound healing complications

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

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 two out of three 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 2week rest).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Angioneurotic oedema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received temsirolimus and ACE inhibitors concomitantly (see section 4.5).

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 moieties, temsirolimus and its metabolite, sirolimus. Therefore, for patients with renal cell carcinoma, continuous administration beyond 57 days with agents that have CYP3A4/5 induction potential should be avoided. For patients with mantle cell lymphoma, it is recommended that coadministration of CYP3A4/5 inducers should be avoided due to the higher dose of temsirolimus (see section 4.5).

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 moieties, 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 TORISEL, vaccination may be less effective. The use of live vaccines should be avoided during treatment with TORISEL. Examples of live vaccines are: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Excipients

This medicinal product (concentrate-diluent mixture) contains 35% volume ethanol (alcohol); i.e., up to 693.5 mg per dose, equivalent to 17.6 ml beer, 7.3 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.

Interaction studies have only been performed in adults.

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Angioneurotic oedema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received temsirolimus and ACE inhibitors concomitantly (see section 4.4).

Agents inducing CYP3A metabolism

Co-administration of TORISEL with rifampicin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus C_max (maximum concentration) and AUC (area under the concentration vs. time curve) after intravenous administration, but decreased sirolimus C_max by 65% and AUC by 56%, compared to TORISEL 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 TORISEL 5 mg with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus C_max or AUC; however, sirolimus AUC increased 3.1fold, and AUC_sum (temsirolimus + sirolimus) increased 2.3fold compared to TORISEL 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 TORISEL 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

In 23 healthy subjects, the concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of temsirolimus was co-administered. No clinically significant effect is anticipated when TORISEL is coadministered with agents that are metabolised by CYP2D6 in patients with renal cell carcinoma. For patients with mantle cell lymphoma, the effect of a 175 or 75 mg temsirolimus dose on CYP2D6 or 3A4 substrates has not been studied. However, based on in vitro studies in human liver microsomes, the plasma concentrations achieved after a 175 mg dose of temsirolimus might possibly lead to inhibition of CYP3A4/5 and CYP2D6 (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 via CYP3A4/5 or CYP2D6 and that have a narrow therapeutic index.

Interactions with drugs that are P-glycoprotein substrates

In an in vitro study, temsirolimus inhibited the transport of Pglycoprotein (P-gp) substrates with an IC₅₀ value of 2 µM. In vivo, the effect of P-gp inhibition has not been investigated, but mean C_max concentrations of temsirolimus are 2.6 µM in MCL patients receiving the 175 mg IV dose of temsirolimus. Therefore, when temsirolimus is coadministered with medications which are P-gp substrates (e.g. digoxin, vincristine, colchicine, and paclitaxel) close monitoring for adverse events related to the co-administered drugs should be observed.

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.

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

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).

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, breastfeeding should be discontinued during therapy.

No studies on the effects on the ability to drive and use machines have been performed.

Due to the different approved posology for RCC and MCL and the dose-dependency of the frequency and severity of undesirable effects, adverse drug reactions are listed separately.

Renal cell carcinoma

A total of 626 patients were randomly assigned in a phase 3, threearm, randomised, openlabel study of Interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFNα. A total of 616 patients received treatment: 200 patients received IFN-α weekly; 208 received TORISEL 25 mg weekly, and 208 patients received a combination of IFN-α and TORISEL weekly. Based on the results of the phase 3 study, elderly patients may be more likely to experience certain adverse reactions, including face oedema and pneumonia.

The most serious reactions observed with TORISEL are hypersensitivity/infusion reactions (including some lifethreatening and rare fatal reactions), hyperglycaemia/glucose intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracerebral bleeding, renal failure, bowel perforation, and wound healing complication.

The most common (30%) adverse reactions (all grades) observed with TORISEL include anaemia, nausea, rash (including rash, pruritic rash, maculopapular rash, pustular rash), anorexia, oedema (including facial oedema and peripheral oedema), and asthenia.

Cataracts have been observed in some patients who received the combination of temsirolimus and interferonα.

See section 4.4 for additional information concerning serious adverse reactions, including appropriate actions to be taken if specific reactions occur.

The following list contains adverse reactions seen in RCC Clinical Trial 1. Only events for which there is at least reasonable suspicion of a causal relationship to intravenous treatment with TORISEL are listed.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions are listed according to the following categories:

Very common: 1/10

Common: 1/100 to <1/10

Uncommon: 1/1,000 to <1/100

*Body system totals are not necessarily the sum of the individual adverse events, since a subject may report two or more different adverse events in the same body system.

**Patients should be advised that treatment with TORISEL may be associated with an increase in blood glucose levels in diabetic and non-diabetic patients.

Mantle cell lymphoma

A total of 54 patients were treated with 175/75 mg TORISEL in the MCL Clinical Trial, a phase 3, threearm, randomised, openlabel study of TORISEL comparing 2 different dosing regimens of temsirolimus with an investigator's choice of therapy in patients with relapsed and/or refractory mantle cell lymphoma. Based on the results of the phase 3 study, elderly patients (65 years) may be more likely to experience certain adverse reactions, including pleural effusion, anxiety, depression, insomnia, dyspnoea, leukopaenia, lymphopaenia, myalgia, arthralgia, taste loss, dizziness, upper respiratory infection, mucositis, and rhinitis.

The most serious reactions observed with TORISEL are thrombocytopaenia, neutropaenia, infections, interstitial lung disease (pneumonitis), bowel perforation, hypersensitivity reactions, and hyperglycaemia/glucose intolerance.

The most common (30%) adverse reactions (all grades) observed with TORISEL include thrombocytopaenia, asthenia, anaemia, diarrhoea, bacterial and viral infections*, rash*, pyrexia, anorexia, epistaxis, mucositis, oedema*, and stomatitis*.

The occurrence of undesirable effects following the dose of 175 mg TORISEL/week for MCL, e.g. grade 3 or 4 infections or thrombocytopaenia, is associated with a higher incidence than that observed with either 75 mg TORISEL/week or conventional chemotherapy.

*See table below for additional terms included with these adverse reactions.

See section 4.4 for additional information concerning serious adverse reactions, including appropriate actions to be taken if specific reactions occur.

The following list contains adverse reactions seen in the MCL Clinical Trial. Only events for which there is at least reasonable suspicion of a causal relationship to intravenous treatment with TORISEL are listed.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions are listed according to the following categories:

Very common: 1/10

Common: 1/100 to <1/10

*Body system totals are not necessarily the sum of the individual adverse events since a subject may report two or more different adverse events in the same body system.

**Grades 3 and 4 (thrombocytopaenia) are defined as 50,000-25,000 platelets/mm³ and <25,000 platelets/mm³, respectively. Grades 3 and 4 (neutropaenia) are defined as 1000-500 neutrophils/mm³ and <500 neutrophils/mm³, respectively.

***Patients should be advised that treatment with TORISEL may be associated with an increase in blood glucose levels in diabetic and non-diabetic patients.

****One case of fatal pneumonitis was reported in a mantle cell lymphoma patient receiving 175/25 mg/week that is not included in this table.

Serious adverse reactions observed in clinical trials of temsirolimus for advanced renal cell carcinoma, but not in clinical trials of temsirolimus for mantle cell lymphoma include: anaphylaxis, impaired wound healing, renal failure with fatal outcomes, and pulmonary embolus.

Adverse reactions for which frequency is undetermined

Angioneurotic oedema-type reactions in some patients who received temsirolimus and ACEinhibitors concomitantly.

There is no specific treatment for TORISEL intravenous overdose. While TORISEL has been safely administered to patients with renal cancer with repeated intravenous doses of temsirolimus as high as 220 mg/m², in MCL, two administrations of 330 mg TORISEL/week in one patient resulted in grade 3 rectal bleeding and grade 2 diarrhoea.

Pharmacotherapeutic group: Protein Kinase Inhibitors; ATC code: L01X E09

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 μM), temsirolimus can bind and inhibit mTOR in the absence of FKBP12. Biphasic dose response of cell growth inhibition was observed. High concentrations resulted in complete cell growth inhibition in vitro, whereas inhibition mediated by FKBP12/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, HIF1 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 antitumour 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

Renal cell carcinoma

The safety and efficacy of TORISEL in the treatment of advanced renal cell carcinoma were studied in the following two randomised clinical trials:

RCC Clinical Trial 1

RCC Clinical Trial 1 was a phase 3, multicentre, threearm, randomised, openlabel study in previously untreated patients with advanced renal cell carcinoma and with 3 or more of 6 preselected prognostic risk factors (less than one year from time of initial renal cell carcinoma 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 one 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 three geographic regions and were randomly assigned (1:1:1) to receive IFNα alone (n = 207), TORISEL alone (25 mg weekly; n = 209), or the combination of IFNα and TORISEL (n = 210).

In RCC Clinical Trial 1, TORISEL 25 mg was associated with a statistically significant advantage over IFNα in the primary endpoint of OS at the 2^nd pre-specified interim analysis (n = 446 events, p = 0.0078). The TORISEL arm showed a 49% increase in median OS compared with the IFNα arm. TORISEL also was associated with statistically significant advantages over IFNα in the secondary endpoints of PFS, TTF, and clinical benefit rate.

The combination of TORISEL 15 mg and IFNα did not result in a significant increase in overall survival when compared with IFNα 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 TORISEL and IFNα resulted in a statistically significant increase in the incidence of certain grade 34 adverse events (weight loss, anaemia, neutropaenia, thrombocytopaenia and mucosal inflammation) when compared with the adverse events observed in the IFNα or TORISELalone arms.

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 TORISEL 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 IFNα. 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 IFNα.

RCC Clinical Trial 2

RCC Clinical Trial 2 was a randomised, doubleblind, multicentre, outpatient trial to evaluate the efficacy, safety, and pharmacokinetics of three dose levels of TORISEL when administered to previously treated patients with advanced renal cell carcinoma. 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 temsirolimus intravenous 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 renal cell carcinoma. 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 (IV) temsirolimus for the treatment of relapsed and/or refractory mantle cell lymphoma were studied in the following phase 3 clinical study.

MCL Clinical Trial

MCL Clinical Trial is a controlled, randomised, open-label, multicenter, outpatient study comparing 2 different dosing regimens of temsirolimus with an investigator's choice of therapy in patients with relapsed and/or refractory mantle cell lymphoma. Subjects with mantle cell lymphoma (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 temsirolimus IV 175 mg (3 successive weekly doses) followed by 75 mg weekly (n = 54), temsirolimus IV 175 mg (3 successive weekly doses) followed by 25 mg weekly (n=54), or the investigator's choice of singleagent treatment (as specified in the protocol; n = 54). Investigator's choice therapies included: gemcitabine (IV: 22 [41.5%]), fludarabine (IV: 12 [22.6%] or oral: 2 [3.8%]), chlorambucil (oral: 3 [5.7%]), cladribine (IV: 3 [5.7%]), etoposide (IV: 3 [5.7%]), cyclophosphamide (oral: 2 [3.8%]), thalidomide (oral: 2 [3.8%]), vinblastine (IV: 2 [3.8%]), alemtuzumab (IV: 1 [1.9%]), and lenalidomide (oral: 1 [1.9%]). The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent radiologist and oncology review. Secondary efficacy endpoints included overall survival (OS) and objective response rate (ORR).

The results for the MCL Clinical Trial are summarized 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 mantle cell lymphoma 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). Overall survival was similar.

Temsirolimus also was associated with statistically significant advantages over investigator's choice in the secondary endpoint of overall response rate (ORR). The evaluations of PFS and ORR were based on blinded independent radiologic assessment of tumour response using the International Workshop Criteria.

^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.

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.

Absorption

Following administration of a single 25 mg intravenous dose of temsirolimus in patients with cancer, mean C_max 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 C_max 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 FKBP12 in blood cells. The mean (standard deviation, SD) dissociation constant (K_d) 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.

Metabolism

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, secotemsirolimus 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 2.7fold that of temsirolimus AUC, due principally to the longer halflife of sirolimus.

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 halflives of temsirolimus and sirolimus were 17.7 hr and 73.3 hr, 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. Possible effects of inhibition of Pgp on elimination of temsirolimus and sirolimus in vivo have not been investigated.

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 C_max concentration of 2.6 μM for temsirolimus in MCL patients receiving the 175 mg dose there is a potential for interactions with concomitantly administered drugs that are substrates of CYP3A4/5 and CYP2D6 in patients treated with the 175 mg dose of temsirolimus (see section 4.5). However, it is unlikely that whole blood concentrations of temsirolimus after IV administration of temsirolimus will inhibit the metabolic clearance of concomitant drugs that are substrates of CYP2C9, CYP2C8, CYP2B6 or CYP2E1.

Special Populations

Hepatic impairment

Temsirolimus and sirolimus pharmacokinetics have been investigated in an open-label, dose-escalation study in 112 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 6 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 levels of temsirolimus and sirolimus exposures in blood (AUC_sum 6580 ng·h/ml), which approximate to those following the 25 mg dose (AUC_sum 7280 ng·h/ml) in patients with normal liver function (see sections 4.2 and 4.4).

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

Temsirolimus and sirolimus pharmacokinetics in the paediatric population have not been investigated.

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.

Concentrate:

Anhydrous ethanol

all-rac-α-Tocopherol (E 307)

Propylene glycol

Anhydrous citric acid (E 330)

Diluent:

Polysorbate 80 (E 433)

Macrogol 400

Anhydrous ethanol

This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.

TORISEL 25 mg/ml concentrate for solution for infusion must not be added directly to aqueous infusion solutions. Direct addition of TORISEL 25 mg/ml concentrate to aqueous solutions will result in precipitation of medicinal product.

Always dilute TORISEL 25 mg/ml concentrate for solution for infusion with the supplied diluent before adding to infusion solutions. TORISEL may only be administered in sodium chloride 9 mg/ml (0.9%) solution for injection after the initial dilution of TORISEL 25 mg/ml concentrate with 1.8 ml of withdrawn diluent.

TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of di(2ethylhexyl) 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.

2 years.

After first dilution of TORISEL 25 mg/ml concentrate with 1.8 ml of withdrawn diluent: 24 hours when stored below 25°C and protected from light.

After further dilution of the concentrate-diluent mixture with sodium chloride 9 mg/ml (0.9%) solution for injection: 6 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 of the diluted medicinal product, see section 6.3.

TORISEL 25 mg/ml concentrate:

Clear glass vial (type 1 glass) with butyl rubber stopper and a plastic flip-top closure sealed with aluminum.

Diluent:

Clear glass vial (type 1 glass) with butyl rubber stopper and a plastic flip-top closure sealed with aluminum.

Pack size: 1 vial of 1.2 ml of TORISEL 25 mg/ml concentrate and 1 vial of 2.2 ml of diluent.

During handling and preparation of admixtures, TORISEL should be protected from excessive room light and sunlight.

TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of di(2ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC).

Therefore, PVC bags and medical devices must not be used for the preparation, storage and administration of TORISEL solutions for infusions.

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

Dilution

TORISEL 25 mg/ml concentrate must be diluted with the supplied diluent before administration in sodium chloride infusion.

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-diluent 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).

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 drugs:

STEP 1: DILUTION OF TORISEL 25 MG/ML CONCENTRATE WITH THE SUPPLIED DILUENT

• Withdraw 1.8 ml of the supplied diluent.

• Inject the 1.8 ml of diluent into the vial of TORISEL 25 mg/ml concentrate, which contains 30 mg of temsirolimus (1.2 ml of concentrate).

• Mix the diluent 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 1.2 ml of TORISEL 25 mg/ml concentrate contains 30 mg of temsirolimus: when the 1.2 ml concentrate is combined with 1.8 ml of withdrawn diluent, a total volume of 3.0 ml is obtained, and the concentration of temsirolimus will be 10 mg/ml. The concentrate-diluent mixture is stable below 25°C for up to 24 hours.

STEP 2 : ADMINISTRATION OF CONCENTRATE-DILUENT MIXTURE IN SODIUM CHLORIDE INFUSION

• Withdraw the required amount of concentrate-diluent 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 resulting solution should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. The admixture of TORISEL in sodium chloride 9 mg/ml (0.9%) solution for injection should be protected from excessive room light and sunlight.

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 60minute period once weekly. 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 composed of glass, polyolefin, or polyethylene 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 inline 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 inline 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 endfilters can be used ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an inline and endfilter is not recommended.

• TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This should be considered during the preparation and administration of TORISEL following constitution. It is important that the recommendations in section 4.2 be followed closely.

Disposal

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

Wyeth Europa Ltd

Huntercombe Lane South

Taplow, Maidenhead

Berkshire SL6 0PH

United Kingdom

EU/1/07/424/001

Date of first authorisation: 19 November 2007

25 January 2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA): http://www.emea.europa.eu/