The SPC has been updated as follows: Update to section 4.8, correction is made to reflect the correct incidence of hypercholesterolemia and Sepsis in the ADR table. As the number of patients is not changed this is a correction of calculation errors

The SPC has been updated as follows:
Section 7 – Change to MAH

Section 10 – Date of revision of text

Section 4.4

·         To add warning and precaution regarding the ADR, Pneumocystis jiroveci pneumonia;

SmPC Section 4.8

·         Added the ADR, Pneumocystis jiroveci pneumonia and made improvements to the pooled ADR table

·         Alignment to QRD 9

update to section 3 (pharmaceutical form),
4.5 (interaction with other medicinal products and other forms of interaction,
4.8 (undesirable effects),
5.2 (pharmacokinetic properties),
6.4 (special precautions for storage) and
6.6 (special precautions for disposal and other handling)

1.         NAME OF THE MEDICINAL PRODUCT

TORISELTorisel^® 30 mg concentrate and diluent for solution for infusion.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Amendment to the text from TORISEL to  Torisel

Excipients with known effects:

1 vial ToriselTORISEL 30 mg concentrate contains 474 mg anhydrous ethanol (anhydrous).
1.8 ml of the diluent, provided contains 358 mg anhydrous ethanol (anhydrous).

For a the full list of excipients, see section 6.1.

4.1    Therapeutic indications

Renal cell carcinoma

ToriselTORISEL is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC) who have at least three of six prognostic risk factors (see section 5.1).

Mantle cell lymphoma

ToriselTORISEL is indicated for the treatment of adult patients with relapsed and/or refractory mantle cell lymphoma ([MCL)] (see section 5.1).

4.2    Posology and method of administration

Amendment to the text from TORISEL to  Torisel

Posology

Patients should be given intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus (see section 4.4).

Treatment with ToriselTORISEL  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

Amendment to the text from temsirolimus to Torisel

Mantle cell lymphoma

Amendment to the text from temsirolimus to Torisel

Dose rReduction lLevels

Temsirolimus dDose mModifications bBased on wWeekly ANC and pPlatelet cCounts

Removed the paragraph  Paediatric population

Elderly population

No specific dose adjustment is necessary.

Patients with rRenal 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).

Patients with hHepatic impairment

Amended the text from IV to intravenous

Added

Paediatric population

There is no relevant use of temsirolimus in the paediatric population in the indication: treatment of renal cell carcinoma and  mantle cell lymphoma.

Temsirolimus should not be used in the paediatric population for the treatment of neuroblastoma, rhabdomyosarcoma or high-grade glioma, because of efficacy concerns based on the available data (see section 5.1).

Method of administration

TORISEL Torisel  must be administered by intravenous (IV) infusion. For instructions on dilution and preparation of the medicinal product before administration, see section 6.6.

Renal cell carcinoma

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

Mantle cell lymphoma

The recommended dose of Torisel 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 (see section 6.6 for instructions on dilution, administration and disposal).

4.3    Contraindications

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

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

4.4    Special warnings and precautions for use

Renal impairment

Amendment to the text from TORISEL to  Torisel

Renal failure

Amendment to the text from TORISEL to  Torisel

Hepatic impairment

CUse caution should be used when treating patients with hepatic impairment.

Temsirolimus is cleared predominantly by the liver. In an open-label, dose-escalation phase I study in 110 subjects with advanced malignancies and either normal or impaired hepatic function, concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. Assessment of AST and bilirubin levels is recommended before initiation of temsirolimus and periodically after.

An increased rate of fatal events was observed in patients with moderate and severe hepatic impairment. The fatal events included those due to progression of disease; however a causal relationship cannot be excluded.

Based on the phase I study, no dose adjustment of temsirolimus is recommended for RCC patients with baseline platelet counts ³ 100x10⁹/l and mild to moderate hepatic impairment (total bilirubin up to 3 times upper limit of normal [ULN] with any abnormality of AST, or as defined by Child-Pugh Class A or B). For patients with RCC and severe hepatic impairment (total bilirubin > 3 times ULN with any abnormality of AST, or as defined by Child-Pugh Class C), the recommended dose for patients who have baseline platelets ³ 100 x 10⁹/l is 10 mg IV intravenous once a week infused over a 30-60 minute period (see section 4.2).

Thrombocytopaenia and neutropaenia

Grades 3 and 4 thrombocytopaenia and/or neutropaenia have been observed in the MCL cClinical tTrial (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.

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. ToriselTemsirolimus 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 ToriselTORISEL 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 ToriselTORISEL 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 ToriselTORISEL 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, Toriseltemsirolimus 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 ToriselTORISEL 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

Amendment to the text from TORISEL to  Torisel

Hyperlipaemia

Amendment to the text from TORISEL to  Torisel

Wound healing complications

Amendment to the text from TORISEL to  Torisel

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 2‑week rest) (see section 4.5).

Vaccinations

Amendment to the text from TORISEL to  Torisel

Excipients

Amendment to the text from TORISEL to  Torisel

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups, such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines. The amount of alcohol in this medicinal product may impair your ability to drive or use machines (see section 4.7).

4.5    Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Concomitant use of temsirolimus with sunitinib

The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) were observed in 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 2‑week rest) (see section 4.4).

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

Amendment to the text from temsirolimus to Torisel

Agents inhibiting CYP3A metabolism

Amendment to the text from temsirolimus to Torisel

Amendment to the text from TORISEL to Torisel

Interaction with medicinal products metabolised by CYP2D6 or CYP3A4

Amendment to the text from temsirolimus to Torisel

Interactions with drugs medicinal products that are P-glycoprotein substrates

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

4.6    Fertility, pregnancy and lactation

Women of childbearing potential/ Contraception in males and females

Amendment to the text from TORISELto Torisel

Pregnancy

Amendment to the text from TORISELto Torisel

4.7    Effects on ability to drive and use machines

Torisel has no known influence on the ability to drive and use machines based on the evidence available.  No studies on the effects on the ability to drive and use machines have been performed.

For patients receiving the higher dose of 175 mg IV intravenous of TORISEL Torisel for the treatment of MCL, the amount of ethanol in this medicinal product may impair your ability to drive or use machines (see section 4.4).

4.8    Undesirable effects

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.

Summary of the safety profile Renal cell carcinoma

A total of 626 patients were randomly assigned in a phase 3, three‑arm, randomised, open‑label study of Interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN‑α. 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 Torisel in clinical trials are hypersensitivity/infusion reactions (including some life‑threatening and rare fatal reactions), hyperglycaemia/glucose intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracerebral bleeding intracranial haemorrhage, renal failure, bowel intestinal perforation, and wound healing complication, thrombocytopenia,  neutropenia (including febrile neutropenia), pulmonary embolism..

The most common (³30%) adverse reactions (all grades) experienced by at least 20% of  the patients in renal cell carcinoma and mantle cell lymphoma registration studiesobserved with TORISEL include anaemia, nausea, rash (including rash, pruritic rash, maculopapular rash, pustular rash), anorexiadecreased appetite, oedema, (including facial oedema and peripheral oedema), and asthenia, fatigue, thrombocytopaenia, diarrhea, pyrexia, epistaxis, mucosal inflammation, stomatitis, vomiting, hyperglycemia, hypercholesterolemia, dysgeusia, pruritus, cough, infection, pneumonia, dyspnoea.

.

Cataracts have been observed in some patients who received the combination of temsirolimus and interferon‑α.

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.

Based on the results of the phase 3 studies, elderly patients may be more likely to experience certain adverse reactions, including face oedema, pneumonia,  pleural effusion, anxiety, depression, insomnia, dyspnoea, leukopaenia, lymphopaenia, myalgia, arthralgia, ageusia, dizziness, upper respiratory infection, mucositis, and rhinitis.

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.

Serious adverse reactions observed in clinical trials of temsirolimus for mantle cell lymphoma, but not in clinical trials of temsirolimus for advanced renal cell carcinoma include: thrombocytopenia,  and neutropenia (including febrile neutropenia).

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

The occurrence of undesirable effects following the dose of 175 mg 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.

Tabulated list of adverse reactions

Adverse reactions that were reported in RCC and MCL patients in the phase 3 studies are listed below (Table 1), by system organ class, frequency and grade of severity (NCI-CTCAE). Within each frequency grouping, undesirable effectsadverse reactions are presented in order of decreasing seriousness.

Adverse reactions are listed according to the following categories:

Very common: ³1/10

Common: ³1/100 to <1/10

Uncommon: ³1/1,000 to <1/100

a, b, c: including one fatal case each

*Most NCI-CTC grade 3 and above reactions observed in clinical trials of temsirolimus for mantle cell lymphoma

** All NCI-CTC grade 3 and above reactions observed in clinical trials of temsirolimus for mantle cell lymphoma

*** Most NCI-CTC all grades reactions observed in clinical trials of temsirolimus for mantle cell lymphoma

**** All NCI-CTC Grade 1 and 2 reactions observed in clinical trials of temsirolimus for mantle cell lymphoma

*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, three‑arm, randomised, open‑label 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 (³65 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 (³30%) 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: ³1/10

Common: ³1/100 to <1/10