Chemical formula: C₅₆H₈₇NO₁₆ Molecular mass: 1,030.287 g/mol PubChem compound: 23724530
Temsirolimus interacts in the following cases:
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.
In 23 healthy subjects the concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of temsirolimus was co-administered. In 36 patients with MCL, including 4 poor metabolisers, the effect of CYP2D6 inhibition after administration of single doses of 175 mg and 75 mg temsirolimus was investigated. Population PK analysis based on sparse sampling indicated no clinically significant interaction effect on AUC and Cmax of the CYP2D6 substrate desipramine. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolised by CYP2D6.
Co-administration of temsirolimus with rifampicin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus maximum concentration (Cmax) and area under the concentration vs. time curve (AUC) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56%, compared to temsirolimus 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).
Co-administration of temsirolimus 5 mg with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus C max or AUC; however, sirolimus AUC increased 3.1-fold, and AUC sum (temsirolimus + sirolimus) increased 2.3-fold compared to temsirolimus 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 temsirolimus with these agents should be avoided.
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.
The effect of a 175 or 75 mg temsirolimus dose on CYP3A4/5 substrates has not been studied. However, in vitro studies in human liver microsomes followed by physiologically-based pharmacokinetic modelling indicate that the blood concentrations achieved after a 175 mg dose of temsirolimus most likely leads to relevant inhibition of CYP3A4/5. Therefore, caution is advised during concomitant administration of temsirolimus at a dose of 175 mg with medicinal products that are metabolised predominantly via CYP3A4/5 and that have a narrow therapeutic index.
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 × 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). 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 × 109/l is 10 mg intravenous once a week infused over a 30-60 minute period.
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 in a clinical drug-drug interaction study, however, recent preliminary data from a Phase 1 study of combined lenalidomide (dose of 25 mg) and temsirolimus (dose of 20 mg) seem to support the in vitro findings and suggest an increased risk of adverse events. Therefore, when temsirolimus is co-administered with medicinal products which are P-gp substrates (e.g. digoxin, vincristine, colchicine, dabigatran, lenalidomide, and paclitaxel) close monitoring for adverse events related to the co-administered medicinal products should be observed.
Temsirolimus should be used with caution in patients with severe renal impairment.
Temsirolimus elimination by the kidneys is negligible; studies in patients with varying renal impairment have not been conducted. 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.
An increased incidence of angioneurotic oedema (including delayed reactions occurring two months following initiation of therapy) has been observed in patients who received temsirolimus or other mTOR inhibitors in combination with an ACE inhibitor (e.g. ramipril) and/or a calcium channel blocker (e.g. amlodipine).
In male rats, decreased fertility and partly reversible reductions in sperm counts were reported.
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.
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).
Grades 3 and 4 thrombocytopenia and/or neutropenia have been observed in the MCL clinical trial. Patients on temsirolimus who develop thrombocytopenia may be at increased risk of bleeding events, including epistaxis. Patients on temsirolimus with baseline neutropenia may be at risk of developing febrile neutropenia. Cases of anaemia have been reported in RCC and MCL. Monitoring of complete blood count is recommended prior to initiating temsirolimus therapy and peridically thereafter.
Temsirolimus dose modifications based on weekly ANC and platelet counts:
| ANC | Platelets | Dose of temsirolimus |
|---|---|---|
| ≥1,0 × 109/l | ≥50 × 109/l | 100% of planned dose |
| <1,0 × 109/l | <50 × 109/l | Holda |
a Upon recovery to ANC ≥1.0 × 109/l (1000 cells/mm³) and platelets to ≥50 × 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 × 109/l and platelets >50 × 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.
Cataracts have been observed in some patients who received the combination of temsirolimus and interferon-α (IFN-α).
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.
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.
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.
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.
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 for RCC, 26% of patients reported hyperglycaemia as an adverse event. In the MCL clinical trial, a Phase 3 clinical trial for MCL, 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.
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.
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.
The potential risk for humans is unknown. Temsirolimus must not be used during pregnancy, unless the risk for the embryo is justified by the expected benefit for the mother.
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.
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 temsirolimus.
Men with partners of childbearing potential should use medically acceptable contraception while receiving temsirolimus.
In male rats, decreased fertility and partly reversible reductions in sperm counts were reported.
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.
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).
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 temsirolimus/week for MCL, e.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.
Adverse reactions that were reported in RCC and MCL patients in the phase 3 studies are listed below, by system organ class, frequency and grade of severity (NCI-CTCAE). Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
*Adverse reactions from clinical trials in RCC (study 3066K1-304) and in MCL (study 3066K1-305):
Adverse reactions that were reported in post-marketing experience are listed below.
*Adverse reactions reported in post-marketing setting:
Rare: Pneumocystis jiroveci pneumonia
Not known: Angioneurotic oedema-type reactions
Not known: Stevens-Johnson syndrome
Not known: Rhabdomyolysis
Angioneurotic oedema-type reactions have been reported in some patients who received temsirolimus and ACE-inhibitors concomitantly.
Cases of PCP, some with fatal outcomes, have been reported.
In a Phase 1/2 study, 71 patients (59 patients, aged from 1 to 17 years old, and 12 patients, aged 18 to 21 years) were administered temsirolimus at doses ranging from 10 mg/m² to 150 mg/m².
The adverse reactions reported by the highest percentage of patients were haematologic (anaemia, leukopenia, neutropenia, and thrombocytopenia), metabolic (hypercholesterolemia, hyperlipaemia, hyperglycaemia, increase of serum aspartate amino transferase (AST) and serum alanine aminotransferase (ALT) plasma levels), and digestive (mucositis, stomatitis, nausea, and vomiting).
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