Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use
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 population

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

Renal impairment/renal failure

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


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

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 1study 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 1study, no dose adjustment of temsirolimus is recommended for RCC patients with baseline platelet counts ≥ 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 ≥ 100 x 109/l is 10 mg intravenous once a week infused over a 30 to 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.

Thrombocytopenia neutropenia and anaemia

Grades 3 and 4 thrombocytopenia and/or neutropenia have been observed in the MCL clinical trial (see section 4.8). Patients on temsirolimus who develop thrombocytopenia may be at increased risk of bleeding events, including epistaxis (see section 4.8). Patients on temsirolimus with baseline neutropenia may be at risk of developing febrile neutropenia. Cases of anaemia have been reported in RCC and MCL (see section 4.8). Monitoring of complete blood count is recommended prior 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 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).

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. 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 an 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 resumed at a slower rate (up to 60 minutes) and should be completed within six hours from the time that temsirolimus 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 temsirolimus 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 forRCC, 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 fatal reports, occurring in patients who received weekly intravenous temsirolimus. Some patients were asymptomatic or had minimal symptoms 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 temsirolimus or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of temsirolimus therapy. Periodical follow-up assessments may be considered. It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms and patients should be advised to report promptly any new or worsening respiratory symptoms. If clinically significant respiratory symptoms develop, temsirolimus administration may be withheld until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Opportunistic infections such as PCP should be considered in the differential diagnosis. Empiric treatment with corticosteroids and/or antibiotics may be considered. For patients who require use of corticosteroids, prophylaxis of PCP should be considered based upon current standard of care.

Hyperlipaemia

The use of temsirolimus was associated with increases in serum triglycerides and cholesterol. In the RCC clinical trial 1, hyperlipaemia was reported as an adverse event in 27% of patients. In the 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 temsirolimus. The known association of temsirolimus with hyperlipaemia may predispose to myocardial infarction.

Wound healing complications

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

Malignancies

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

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 2 out of 3 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).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or calcium channel blockers 
Caution should be exercised when temsirolimus is given concomitantly with ACE inhibitors (e.g.
ramipril) and/or calcium channel blockers (e.g. amlodipine). An increased risk of angioneurotic oedema- (including delayed reactions occurring two months following initiation of therapy) is possible in patients who receive temsirolimus concomitantly with an ACE inhibitor and/or a calcium channel blocker(see sections 4.5 and 4.8).


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, drug substances temsirolimus and its metabolite, sirolimus. Therefore, for patients with RCC, continuous administration beyond 5-7 days with agents that have CYP3A4/5 induction potential should be avoided. For patients with MCL, 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 drug substances, 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).

Agents affecting P-glycoprotein

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


Vaccinations
Immunosuppressants may affect responses to vaccination. During treatment with temsirolimus, vaccination may be less effective. The use of live vaccines should be avoided during treatment with temsirolimus. Examples of live vaccines are: measles, mumps, rubella, oral polio, Bacillus Calmette- Guérin (BCG), yellow fever, varicella, and TY21a typhoid vaccines.

Excipient information

Ethanol
After first dilution the concentrate with 1.8 ml of the supplied diluent, the concentrate-diluent mixture contains 35% volume ethanol (alcohol), i.e., up to 0.693 g per 25 mg dose of temsirolimus, equivalent to 18 ml beer or 7 ml wine per dose. Patients administered the higher dose of 175 mg of temsirolimus for the initial treatment of MCL may receive up to 4.85 g of ethanol (equivalent to 122 ml beer or 49 ml wine per dose).

An example of ethanol exposure based on maximum single daily dose (see section 4.2) is as follows: • Administration of the higher dose of 175 mg of temsirolimus for the initial treatment of MCL to an adult weighing 70 kg would result in exposure to 69.32 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 11.5 mg/100 ml.
For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml.


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

The ethanol content in this medicinal product should be carefully considered in the following patient groups who may be at higher risk of ethanol-related adverse effects:
• Pregnant or breast-feeding women (see section 4.6)
• Patients suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups, such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines.
Co-administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, particularly in young children with low or immature metabolic capacity.

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

Propylene glycol
Torisel contains propylene glycol (see section 2). An example of propylene glycol exposure based on maximum single daily dose (see section 4.2) is as follows: Administration of the higher dose of 175 mg of temsirolimus for the initial treatment of MCL to an adult weighing 70 kg would result in a propylene glycol exposure of 50.33 mg/kg/day.

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

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

Propylene glycol doses of ≥1 mg/kg/day may induce serious adverse effects in neonates, while doses of ≥50 mg/kg/day may induce adverse effects in children less than 5 years old and should only be administered on a case by case basis.

Administration of ≥50 mg/kg/day of propylene glycol to pregnant or lactating women should only be considered on a case by case basis (see section 4.6).

Effects on Driving

4.7         Effects on ability to drive and use machines

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

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