Torisel

This medicinal product must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products. 4). Treatment with Torisel should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Renal cell carcinoma The recommended dose of temsirolimus for advanced RCC is 25 mg administered by intravenous infusion over a 30 to 60 minute period once a week. Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction of temsirolimus therapy.

If a suspected reaction is not manageable with dose delays, then temsirolimus may be reduced by 5 mg/week decrements. Mantle cell lymphoma The recommended dosing regimen of temsirolimus for MCL is 175 mg, infused over a 30 to 60 minute period once a week for 3 weeks followed by weekly doses of 75 mg, infused over a 30 to 60 minute period.

The starting dose of 175 mg was associated with a significant incidence of adverse events and required dose reductions/delays in the majority of patients. The contribution of the initial 175 mg doses to the efficacy outcome is currently not known.

Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction of temsirolimus therapy according to the guidelines in the following tables. If a suspected reaction is not manageable with dose delays and/or optimal medical therapy, then the dose of temsirolimus should be reduced according to the dose reduction table below.

Dose reduction levels Dose reduction level Starting dose 175 mg Continuing dosea 75 mg -1 75 mg 50 mg -2 50 mg 25 mg a In the MCL clinical trial, up to two dose level reductions were allowed per patient. 0 x 109/l (1000 cells/mm3) and platelets to 50 x 109/l (50,000 cells/mm3), the doses should be modified to the next lower dose level according to the table above.

0 x 109/l and platelets 50 x 109/l on the new dose reduction level, then the next lower dose should be given once the counts have recovered.

Abbreviation:

ANC = absolute neutrophil count. Special populations Elderly No specific dose adjustment is necessary in elderly patients. 4 Renal impairment No dose adjustment is recommended in patients with renal impairment. 4). 4). No dose adjustment is recommended for patients with advanced -RCC and mild to moderate hepatic impairment.

2). No dose adjustment is recommended for patients with MCL and mild hepatic impairment. 3). Paediatric population There is no relevant use of temsirolimus in the paediatric population for the indications of RCC and MCL. 1). Method of administration Torisel is for intravenous use only.

The diluted solution must be administered by intravenous infusion. 8 ml of the supplied solvent to achieve a concentration of temsirolimus of 10 mg/ml. 9%) solution for injection. 6.

Summary of the safety profile The most serious reactions observed with temsirolimus in clinical trials are hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), hyperglycaemia/glucose intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracranial haemorrhage, renal failure, intestinal perforation, wound healing complication, thrombocytopenia, neutropenia (including febrile neutropenia), pulmonary embolism.

The adverse reactions (all grades) experienced by at least 20% of the patients in RCC and MCL registration studies include anaemia, nausea, rash (including rash, pruritic rash, maculopapular rash, pustular rash), decreased appetite, oedema asthenia, fatigue, thrombocytopenia, diarrhoea, pyrexia, epistaxis, mucosal inflammation, stomatitis, vomiting, hyperglycaemia, hypercholesterolemia, dysgeusia, pruritus, cough, infection, pneumonia, dyspnoea.

Cataracts have been observed in some patients who received the combination of temsirolimus and IFN-α. Based on the results of the phase 3 studies, elderly patients may be more likely to experience certain adverse reactions, including face oedema, pneumonia, pleural effusion, anxiety, depression, insomnia, dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, ageusia, dizziness, upper respiratory infection, mucositis, and rhinitis.

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

Serious adverse reactions observed in clinical trials of temsirolimus for MCL, but not in clinical trials of temsirolimus for advanced RCC include: thrombocytopenia, and neutropenia (including febrile neutropenia). 4 for additional information concerning serious adverse reactions, including appropriate actions to be taken if specific reactions occur.

g. Grade 3 or 4 infections or thrombocytopenia, is associated with a higher incidence than that observed with either 75 mg temsirolimus/week or conventional chemotherapy. Tabulated list of adverse reactions Adverse reactions that were reported in RCC and MCL patients in the phase 3 studies are listed below (Table 1), by system organ class, frequency and grade of severity (NCI-CTCAE).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 1) Common Gastrointestinal haemorrhage (including anal, rectal, haemorrhoidal, lip, and mouth haemorrhage, gingival bleeding) 16 […]

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. 1). Elderly Based on the results of a Phase 3 study in RCC, elderly patients (65 years of age) may be more likely to experience certain adverse reactions, including oedema, diarrhoea, and pneumonia.

Based on the 5 results of a Phase 3 study in MCL, elderly patients (65 years of age) may be more likely to experience certain adverse reactions, including pleural effusion, anxiety, depression, insomnia, dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, taste loss, dizziness, upper respiratory infection, mucositis, and rhinitis.

2). Temsirolimus has not been studied in patients undergoing haemodialysis. 8). Hepatic impairment Caution should be used when treating patients with hepatic impairment. Temsirolimus is cleared predominantly by the liver. In an open-label, dose-escalation Phase 1 study in 110 subjects with advanced malignancies and either normal or impaired hepatic function, concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated aspartate aminotransferase (AST) or bilirubin levels.

Assessment of AST and bilirubin levels is recommended before initiation of temsirolimus and periodically after. An increased rate of fatal events was observed in patients with moderate and severe hepatic impairment. The fatal events included those due to progression of disease; however a causal relationship cannot be excluded.

Based on the Phase 1 study, no dose adjustment of temsirolimus is recommended for RCC patients with baseline platelet counts 100 x 109/l and mild to moderate hepatic impairment (total bilirubin up to 3 times upper limit of normal [ULN] with any abnormality of AST, or as defined by Child-Pugh Class A or B).

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.

8). 8). Patients on temsirolimus with baseline neutropenia may be at risk of developing febrile neutropenia. 8). Monitoring of complete blood count is recommended prior to initiating temsirolimus therapy and peridically thereafter. Infections Patients may be immunosuppressed and should be carefully observed for the occurrence of infections, including opportunistic infections.

Among patients receiving 175 mg/week for the treatment of MCL, infections (including Grade 3 and 4 infections) were substantially increased compared to lower doses and compared to conventional chemotherapy. Cases of pneumocystis jiroveci pneumonia (PCP) some with fatal outcomes, have been reported in patients who received temsirolimus, many of whom also 6 received corticosteroids or other immunosuppressive agents.

Prophylaxis of PCP should be considered for patients who require concomitant use of corticosteroids or other immunosuppressive agents based upon current standard of care. Cataracts Cataracts have been observed in some patients who received the combination of temsirolimus and interferon-α (IFN-α).

8). These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored early during the infusion and appropriate supportive care should be available. The temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.

A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions. If a patient develops a hypersensitivity reaction during the temsirolimus infusion despite the premedication, the infusion must be stopped and the patient observed for at least 30 to 60 minutes (depending on the severity of the reaction).

At the discretion of the physician, treatment may be resumed after the administration of an H1-receptor antagonist (diphenhydramine or similar antihistamine) and a H2-receptor antagonist (intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the temsirolimus infusion.

Administration of corticosteroids may be considered; however, the efficacy of corticosteroid treatment in this setting has not been established. The infusion may then be […]

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