TORISEL 30 mg concentrate and diluent for solution for infusion

  • Name:

    TORISEL 30 mg concentrate and diluent for solution for infusion

  • Company:
    info
  • Active Ingredients:

    Temsirolimus

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

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Pfizer Healthcare Ireland

Pfizer Healthcare Ireland

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 9 January 2019 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 9 January 2019 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

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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

Updated on 10 August 2018 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 10 August 2018 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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

Section 10 – Date of revision of text

Updated on 4 April 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 4 April 2018 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may not be renewed (A)

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The SPC has been updated as follows:SPC Section 4.3 to make use in moderate or severe hepatic impairment an absolute CI,: minor editorial changes in section 4.8 and 6.6

Updated on 28 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 28 March 2018 PIL

Reasons for updating

  • Change to section 4 - how to report a side effect
  • Change to information for healthcare professionals

Updated on 4 August 2017 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.1 - List of excipients
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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The SPC has been updated as follows: Sections 1-3, 4.2-4.9, 5.1, 5.2, 6.1-6.6, 9, 10  QRD 10 updates and licence renewal

Updated on 4 August 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 25 July 2017 PIL

Reasons for updating

  • Change to Section 1 - what the product is
  • Change to section 1 - what the product is used for
  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - use in children and adolescents
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 2 - driving and using machines
  • Change to section 2 - excipient warnings
  • Change to section 3 - how to take/use
  • Change to section 4 - possible side effects
  • Change to section 5 - how to store or dispose
  • Change to section 6 - what the product contains
  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 9 March 2017 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The SPC has been updated as follows, to change revision date only due to a change in annex, and update LR contact details

Updated on 6 March 2017 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 26 January 2017 SmPC

Reasons for updating

  • Product/presentation re-marketed

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Reintroduction of Torisel UK PI at request of  regional team to incorporate updates resulting previous spc updates to section 4.4 and 4.5 to update information related to a possible increased risk of angioedema in patients taking mTOR  inhibitors in combination with ramipril and/or amlodipine; no submission  required as not associated to a new update to SPC

Updated on 20 January 2017 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The SPC has been updated as follows: Sections 4.4 and 4.5 to update information related to a possible increased risk of angioedema in patients taking mTOR  inhibitors in combination with ramipril and/or amlodipine

Updated on 12 January 2017 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 6 - date of revision

Updated on 29 January 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The SPC has been updated as follows:

. Update to address EMEA/H/C/PSUSA/00002887/201503: Section 4.4 of the SmPC was updated to add warnings on myocardial infarction, anaemia and malignancies.

. Annual CD. Sections 4.5 and 5.2 of the SmPC were updated.

Updated on 28 January 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision

Updated on 26 June 2015 PIL

Reasons for updating

  • Change to further information section
  • Change to date of revision

Updated on 17 November 2014 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The SPC has been updated as follows

Additional information on the patients with MCL, and  the effect of CYP2D6 inhibition after administration of single doses. Population PK analysis based on sparse sampling indicated no clinically significant interaction effect on AUC and Cmax of the CYP2D6 substrate desipramine.

Updated on 11 November 2014 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision
  • Correction of spelling/typing errors

Updated on 6 December 2013 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

section 4.8

Updated on 27 November 2013 PIL

Reasons for updating

  • Change to date of revision

Updated on 5 August 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 31 July 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision
  • Addition of marketing authorisation holder
  • Improved electronic presentation

Updated on 27 March 2013 PIL

Reasons for updating

  • Change to date of revision
  • Change to name of manufacturer

Updated on 28 January 2013 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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)

Updated on 25 January 2013 PIL

Reasons for updating

  • Change to storage instructions
  • Change to drug interactions
  • Change to date of revision
  • Change to marketing authorisation holder

Updated on 9 October 2012 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

update to sections1,2,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5.1,5.2,6.2,6.3,6.4,6.5,6.6,9,10

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

 

Dose rReduction lLevel

Starting dDose

175 mg

Continuing dDosea

75 mg

-1

75 mg

50 mg

-2

50 mg

25 mg

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

 

Temsirolimus dDose mModifications bBased on wWeekly ANC and pPlatelet cCounts

 

ANC

Platelets

Dose of tTemsirolimus

³1.0 x 109/l

³50 x 109/l

100% of planned dose

<1.0 x 109/l

<50 x 109/l

Holda

a Upon recovery to ANC ³1.0 x 109/l (1000 cells/mm3) and platelets to ³50 x 109/l (50,000 cells/mm3), the doses should be modified to the next lower dose level according to the table above. If the patient cannot maintain ANC >1.0 x 109/l and platelets >50 x 109/l on the new dose reduction level, then the next lower dose should be given once the counts have recovered.

Abbreviation: ANC = absolute neutrophil count.

 

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 Cmax 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

 

Table 1: adverse reactions

From clinical trials in RCC (study 3066K1-304) and in MCL (study 3066K1-305)

 

 

System
organ class

 

Frequency

 

Adverse reactions

All grades

n (%)

Grade

3 & 4
n (%)

Infections and infestations

Very common

 

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

91 (28.3)

18 (5.6)

Pneumonia (including Interstitial pneumonia)

35 (10.9)

16 (5.0)

Common

 

Sepsis* (including, septic shock)

5 (1.5)

5 (1.5)

Candidiasis (including oral and anal candidiasis) and fungal infection/fungal skin infections

16 (5.0)

0 (0.0)

Urinary tract infection (including cystitis)

29 (9.0)

6 (1.9)

Upper respiratory tract infection

26 (8.1)

0 (0.0)

Pharyngitis **

6 (1.9)

0 (0.0)

Sinusitis

10 (3.1)

0 (0.0)

Rhinitis

7 (2.2)

0 (0.0)

Folliculitis

4 (1.2)

0 (0.0)

Uncommon

Laryngitis

1 (0.3)

0 (0.0)

Blood and lymphatic system disorders

Very common

 

Neutropaenia

46 (14.3)

30 (9.3)

Thrombocytopaenia***

97 (30.2)

56 (17.4)

Anaemia

132(41.1)

48 (15)

Common

 

Leukopoenia ***

29 (9.0)

10 (3.1)

Lymphopaenia

25 (7.8)

16 (5.0)

Immune system disorders

Common

Hypersensitivity reactions / drug hyperensitiviy

24 (7.5)

1 (0.3)

Metabolism and nutrition disorders

Very common

 

Hyperglycaemia

63 (19.6)

31 (9.7)

Hypercholesterolaemia

60 (18.79)

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)

Hyphosphataemia

26 (8.1)

14 (4.4)

Hyperlipidaemia

4 (1.2)

0 (0.0)

Psychiatric disorders

Very Common

Insomnia

45 (14.0)

1 (0.3)

Common

 

Depression

16 (5.0)

0 (0.0)

Anxiety

28 (8.7)

0 (0.0)

Nervous system disorders

Very common

 

Dysgeusia

55 (17.1)

0 (0.0)

Headache

55 (17.1)

2 (0.6)

Common

 

Dizziness

30 (9.3)

1 (0.3)

Paresthaesia

21 (6.5)

1 (0.3)

Ageusia

6 (1.9)

0 (0.0)

Uncommon

 

Intracranial haemorrhage

1 (0.3)

1 (0.3)

Somnolence

8 (2.5)

1 (0.3)

Eye disorders

 

Common

Conjunctivitis (including conjunctivitis, lacrimal disorder)

16 (6.0)

1 (0.3)

Uncommon

Eye haemorrhage

3 (0.9)

0 (0.0)

Cardiac disorders

Uncommon

Pericardial effusion

3 (0.9)

1 (0.3)

Vascular disorders

Common

 

 

Venous thromboembolism (including deep vein thrombosis, venous thrombosis)

7 (2.2) 

4 (1.2)

Thrombophlebitis

4 (1.2)

0 (0.0)

Hypertension

20 (6.2)

3 (0.9)

Respiratory, thoracic and mediastinal disorders

Very common

 

Dyspnoea

79 (24.6)

27 (8.4)

Epistaxis ***

69 (21.5)

1 (0.3)

Cough

93 (29)

3 (0.9)

Common

 

Pneumonitis a

7 (2.2)

2 (0.6)

Interstitial lung disease

6 (1.9)

3 (0.9)

Pleural effusion

19 (5.9)

9 (2.8)

Uncommon

Pulmonary embolism b

2 (0.6)

1 (0.3)

Gastrointestinal disorders

Very common

 

Nausea

109 (34.0)

5 (1.6)

Diarrhoea

109(34.0)

16 (5.0)

Stomatitis

67 (20.9)

3 (0.9)

Vomiting

57 (17.8)

4 (1.2)

Constipation

56 (17.4)

0 (0.0)

Abdominal pain

56 (17.4)

10 (3.1)

Common

 

 

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

16 (5.0)

4 (1.2)

Gastritis ***

7 (2.1)

2 (0.6)

Dysphagia

13 (4.0)

0 (0.0)

Abdominal distension

14 (4.4)

1 (0.3)

Aphthous stomatitis

15 (4.7)

1 (0.3)

Oral pain

9 (2.8)

1 (0.3)

Gingivitis

6 (1.9)

0 (0.0)

Uncommon

Intestinal/duodenal perforation

2 ( 0.6)

1 (0.3)

Skin and subcutaneous tissue disorders

Very common

 

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

138 (43.0)

16 (5.0)

Pruritus (including pruritus generalised)

69 (21.5)

4 (1.2)

Dry skin

32 (10.0)

1 (0.3)

Common

Dermatitis

6 (1.9)

0 (0.0)

Exfoliative rash

5 (1.6)

0 (0.0)

Acne

15 (4.7)

0(0.0)

Nail disorder

24 (8.1)

0 (0.0)

Ecchymosis****

5 (1.6)

0 (0.0)

Petechiae

4 (1.2)

0 (0.0)

Musculoskeletal and connective tissue disorders

Very common

 

Arthralgia

50 (15.6)

2 (0.6)

Back pain

53 (16.5)

8 (2.5)

Common

Myalgia

19 ( 5.9)

0 (0.0)

Renal and urinary disorders

Common

Renal failurec

5 (1.6)

0 (0.0)

General disorders and administration site conditions

Very common

 

Fatigue

133 (41.4)

31 (9.7)

Oedema (including generalized oedema, facial oedema, peripheral oedema, scrotal oedema, genital oedema)

122 (38.0)

11 (3.4)

Asthenia

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, 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

 

Adverse Reactions in RCC Clinical Trial 1

 

System
Organ Class

 

Frequency

 

Adverse Reactions

All Grades

n (%)

Grade

3 & 4
n (%)

Infections and infestations

Very common

Bacterial and viral infections (including infection, cellulitis, herpes zoster, herpes simplex, bronchitis, sinusitis, abscess)*

42 (20)

6 (3)

Very common

Urinary tract infection (including dysuria, haematuria, cystitis, urinary frequency, urinary tract infection)*

31 (15)

4 (2)

Very common

Pharyngitis

25 (12)

0 (0)

Very common

Rhinitis

20 (10)

0 (0)

Common

Pneumonia

17 (8)

5 (2)

Common

Upper respiratory tract infection

14 (7)

0 (0)

Common

Folliculitis

4 (2)

0 (0)

Blood and lymphatic system disorders

Very common

Thrombocytopaenia

28 (14)

3 (1)

Very common

Anaemia

94 (45)

41 (20)