1. Name Of The Medicinal Product
TORISEL
2. Qualitative And Quantitative Composition
Each vial of TORISEL concentrate contains 30 mg temsirolimus.
After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the concentration of temsirolimus is 10 mg/ml (see section 4.2).
Excipients:
1 vial TORISEL 30 mg concentrate contains 474 mg anhydrous ethanol.
1.8 ml of the diluent, provided contains 358 mg anhydrous ethanol.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Concentrate and diluent for solution for infusion (sterile concentrate).
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.
4. Clinical Particulars
4.1 Therapeutic Indications
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).
4.2 Posology And Method Of Administration
TORISEL must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.
The vial of TORISEL concentrate must first be diluted with 1.8 ml of diluent withdrawn from the supplied vial to achieve a concentration of temsirolimus of 10 mg/ml. Withdraw the required amount of the temsirolimus-diluent mixture ( 10 mg/ml) and then inject rapidly into sodium chloride 9 mg/ml (0.9%) solution for injection.
For instructions on preparation and to help ensure correct dosing, see section 6.6.
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.
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 60-minute 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
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a In the MCL Clinical Trial, up to two dose level reductions were allowed per patient.
Temsirolimus Dose Modifications Based on Weekly ANC and Platelet Counts
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a Upon recovery to ANC 9/l (1000 cells/mm3) and platelets to 9/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.
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).
Elderly population
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 9/l is 10 mg IV once a week infused over a 30-60 minute period (see section 5.2).
Method of administration
TORISEL must be administered by intravenous (IV) infusion. For instructions on dilution and preparation of the medicinal product before administration, see section 6.6.
4.3 Contraindications
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).
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 population
Based on the results of a phase 3 study in renal cell carcinoma, elderly patients (
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
Use caution 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 9/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 9/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 fatal reports, occurring in patients who received weekly intravenous TORISEL. 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 TORISEL 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 TORISEL 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, consider withholding TORISEL administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered.
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 2-week 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 5-7 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
After first dilution of TORISEL 30 mg concentrate with 1.8 ml of withdrawn diluent, the concentrate-diluent mixture contains 35% volume ethanol (alcohol); i.e., up to 0.693 g per 25 mg dose of TORISEL, equivalent to 17.6 ml beer, 7.3 ml wine per dose. Patients administered the higher dose of 175 mg of TORISEL for the initial treatment of MCL may receive up to 4.85 g of ethanol (equivalent to 123 ml beer, 51 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. 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 Cmax (maximum concentration) and AUC (area under the concentration vs. time curve) after intravenous administration, but decreased sirolimus Cmax 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 Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and AUCsum (temsirolimus + sirolimus) increased 2.3-fold 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 co-administered 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 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 dose of temsirolimus. Therefore, when temsirolimus is co-administered 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.
4.6 Pregnancy And Lactation
Women of childbearing potential/ Contraception in males and females
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).
Pregnancy
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 (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.
Breastfeeding
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, breast-feeding should be discontinued during therapy.
Fertility
In male rats, decreased fertility and partly reversible reductions in sperm counts were reported (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
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 of 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.
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 are hypersensitivity/infusion reactions (including some life-threatening 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 (
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.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions are listed according to the following categories:
Very common:
Common:
Uncommon:
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