Temsirolimus

Temsirolimus is a selective inhibitor of the mammalian target of rapamycin (mTOR). Its main metabolite, sirolimus, is equally potent and contributes to the effect.

Mechanism of Action

• FKBP-12 binding: temsirolimus binds the intracellular protein FKBP-12, and the protein–drug complex binds and inhibits mTOR, the kinase that controls cell division. At high concentrations in vitro it can also inhibit mTOR without FKBP-12.
• Cell-cycle arrest: inhibiting mTOR delays tumour cells in G1 at nanomolar concentrations and arrests growth at micromolar ones, by selectively disrupting the translation of cell-cycle proteins such as D-type cyclins, c-myc and ornithine decarboxylase. It blocks the phosphorylation of the translation factors 4E-BP1 and S6K, which lie downstream of mTOR in the PI3 kinase/AKT pathway.
• Hypoxia pathway: mTOR also regulates the translation of hypoxia-inducible factors HIF-1 and HIF-2 alpha, and through them vascular endothelial growth factor (VEGF). Lower HIF and VEGF levels in the tumour or its surroundings may impair vessel development and add to the anti-tumour effect; in renal cell carcinoma cell lines temsirolimus reduced HIF-1, HIF-2 alpha and VEGF.

Pharmacokinetics

• Exposure: after a single 25 mg intravenous dose in patients with cancer, mean whole-blood Cmax was 585 ng/mL and mean AUC 1,627 ng·h/mL. With 175 mg weekly for 3 weeks followed by 75 mg weekly, the estimated whole-blood Cmax at the end of infusion was 2,457 ng/mL in week 1 and 2,574 ng/mL in week 3.
• Distribution: blood concentrations decline in several phases, and distribution reflects preferential binding to FKBP-12 in blood cells. After a 25 mg dose the mean steady-state volume of distribution in whole blood was 172 L. About 87% is bound to plasma proteins in vitro.
• Metabolism: mainly through CYP3A4 in the liver. Sirolimus is the principal metabolite in humans, with an AUC 2.7 times that of temsirolimus after a 25 mg dose because its half-life is longer. Other pathways seen in vitro are hydroxylation, reduction and demethylation.
• Elimination: mean systemic clearance from whole blood was 11.4 L/h; mean half-lives were 17.7 hours for temsirolimus and 73.3 hours for sirolimus. About 78% of a radiolabelled dose was recovered in faeces and 4.6% in urine. Sulphation and glucuronidation are not major elimination pathways.
• Hepatic impairment: levels of temsirolimus and sirolimus were higher in patients with raised AST or bilirubin.

• Renal cell carcinoma (RCC): first-line treatment of adult patients with advanced RCC who have at least three of six prognostic risk factors.
• Mantle cell lymphoma (MCL): treatment of adult patients with relapsed and/or refractory MCL.

• Hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80 or any of the excipients.
• Use in patients with mantle cell lymphoma who have moderate or severe hepatic impairment.

The most serious reactions in clinical trials were hypersensitivity and infusion reactions (including some life-threatening and rarely fatal ones), hyperglycaemia and glucose intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracranial haemorrhage, renal failure, intestinal perforation, wound-healing complications, thrombocytopenia, neutropenia (including febrile neutropenia) and pulmonary embolism. Reactions in at least 20% of patients in the registration studies include anaemia, nausea, rash, decreased appetite, oedema, asthenia, fatigue, thrombocytopenia, diarrhoea, pyrexia, epistaxis, mucosal inflammation, stomatitis, vomiting, hyperglycaemia, hypercholesterolaemia, dysgeusia, pruritus, cough, infection, pneumonia and dyspnoea. Reactions are dose-dependent, and grade 3 or 4 infections and thrombocytopenia were more frequent with the 175 mg starting dose in MCL than with 75 mg or conventional chemotherapy.

Very common (≥1/10): bacterial and viral infections (for example cellulitis, herpes zoster, oral herpes, influenza, bronchitis, abscess, wound infection), pneumonia; neutropenia, thrombocytopenia, anaemia; hyperglycaemia, hypercholesterolaemia, hypertriglyceridaemia, decreased appetite, hypokalaemia; insomnia; dysgeusia, headache; dyspnoea, epistaxis, cough; nausea, diarrhoea, stomatitis, vomiting, constipation, abdominal pain; rash, pruritus, dry skin; arthralgia, back pain; fatigue, oedema, asthenia, mucosal inflammation, pyrexia, pain, chills, chest pain; increased serum creatinine.

Common (≥1/100 to <1/10): sepsis (including septic shock), candidiasis and other fungal infections, urinary tract infection, upper respiratory tract infection, pharyngitis, sinusitis, rhinitis, folliculitis; leukopenia, lymphopenia; allergic or hypersensitivity reactions; diabetes mellitus, dehydration, hypocalcaemia, hypophosphataemia, hyperlipaemia; depression, anxiety; dizziness, paraesthesia, somnolence, ageusia; conjunctivitis; venous thromboembolism (including deep vein thrombosis), thrombophlebitis, hypertension; interstitial lung disease, pleural effusion; gastrointestinal haemorrhage, gastritis, dysphagia, abdominal distension, aphthous stomatitis, oral pain, gingivitis; dermatitis, exfoliative rash, acne, nail disorders, ecchymosis, petechiae; myalgia; renal failure; increased aspartate and alanine aminotransferases.

Uncommon (≥1/1,000 to <1/100): laryngitis; intracranial haemorrhage; eye haemorrhage; pericardial effusion; pulmonary embolism; intestinal (including duodenal) perforation; impaired wound healing.

Rare (≥1/10,000 to <1/1,000): Pneumocystis jirovecii pneumonia (post-marketing; some cases fatal).

Not known: angioneurotic oedema-type reactions (reported in some patients who were also taking an ACE inhibitor); Stevens-Johnson syndrome; rhabdomyolysis (post-marketing).

Cataracts have been seen in some patients who received temsirolimus with interferon-α. Elderly patients may be more likely to have oedema, diarrhoea, pneumonia and, in MCL, pleural effusion, anxiety, depression, insomnia, dyspnoea, leukopenia, lymphopenia, myalgia, arthralgia, taste loss, dizziness, upper respiratory infection, mucositis and rhinitis.

• Sunitinib: the combination caused dose-limiting toxicity (grade 3 or 4 erythematous maculopapular rash, and gout or cellulitis needing hospitalisation) in 2 of 3 patients in the first cohort of a phase 1 study. See the SmPC before considering the combination.
• ACE inhibitors and calcium channel blockers (for example ramipril, amlodipine): increased incidence of angioneurotic oedema, including delayed reactions two months after starting; use with caution.
• CYP3A4/5 inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, St John’s wort): rifampicin cut sirolimus Cmax by 65% and AUC by 56%. In RCC, continuous use beyond 5–7 days should be avoided; in MCL, because of the higher dose, co-administration should be avoided.
• Strong CYP3A4 inhibitors (nelfinavir, ritonavir, itraconazole, ketoconazole, voriconazole, nefazodone): ketoconazole raised sirolimus AUC 3.1-fold and the combined temsirolimus and sirolimus AUC 2.3-fold. Avoid the combination.
• Moderate CYP3A4 inhibitors (for example diltiazem, verapamil, clarithromycin, erythromycin, aprepitant, amiodarone): use only with caution at 25 mg, and avoid at doses above 25 mg.
• P-glycoprotein inhibitors: cannabidiol, a P-gp inhibitor, raised exposure to another mTOR inhibitor about 2.5-fold; monitor for side effects and adjust the temsirolimus dose as needed. Dose adjustment may be needed with other P-gp inhibitors.
• P-glycoprotein substrates (for example digoxin, vincristine, colchicine, dabigatran, lenalidomide, paclitaxel): temsirolimus inhibits P-gp in vitro; monitor closely for adverse events of the co-administered medicine.
• CYP3A4/5 substrates: at the 175 mg dose, inhibition of CYP3A4/5 is likely, so take care with medicines metabolised mainly by CYP3A4/5 that have a narrow therapeutic index. No clinically significant effect is expected on CYP2D6 substrates.
• Amphiphilic agents (for example amiodarone, statins): combined use could possibly raise the risk of amphiphilic pulmonary toxicity.
• Vaccines: see Vaccination below; live vaccines should be avoided.
• Food: avoid grapefruit and St John’s wort, which change CYP3A4 metabolism.

Torisel must be given under the supervision of a physician experienced in the use of antineoplastic medicinal products. It is for intravenous use only, as an infusion. The vial of concentrate is first diluted with 1.8 mL of the supplied solvent to give 10 mg/mL; the required amount of this mixture is withdrawn and rapidly injected into sodium chloride 9 mg/mL (0.9%) solution for injection (preparation details are in section 6.6 of the SmPC). Treatment continues until the patient no longer benefits clinically or unacceptable toxicity occurs.

Premedication

Patients should receive intravenous diphenhydramine 25 mg to 50 mg (or a similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus.

Recommended Dose

• Renal cell carcinoma: 25 mg by intravenous infusion over 30 to 60 minutes once a week.
• Mantle cell lymphoma: 175 mg infused over 30 to 60 minutes once a week for 3 weeks, followed by 75 mg weekly. The 175 mg starting dose was associated with many adverse events and needed dose reductions or delays in most patients; the contribution of these initial doses to efficacy is not known.

Dose Adjustments

• RCC: if a suspected reaction cannot be managed with dose delays, reduce by 5 mg/week decrements.
• MCL: reduce according to the dose-level table. From the 175 mg starting dose, level −1 is 75 mg and level −2 is 50 mg; from the 75 mg continuing dose, level −1 is 50 mg and level −2 is 25 mg. In the MCL trial up to two reductions per patient were allowed.
• Blood counts: the dose is held while neutrophil or platelet counts are below the thresholds in the SmPC table, and once counts recover it is given at the next lower dose level; if the new level cannot be maintained, the next lower dose is used after counts recover.

Special Populations

• Elderly: no specific dose adjustment.
• Renal impairment: no dose adjustment; use with caution in severe impairment.
• Hepatic impairment: use with caution. No adjustment for RCC with mild to moderate impairment. For RCC with severe impairment (total bilirubin above 3 times the upper limit of normal with any AST abnormality, or Child-Pugh C), the recommended dose is 10 mg once weekly, for patients whose baseline platelet count meets the threshold given in the SmPC. In MCL, no adjustment for mild impairment, and temsirolimus must not be used with moderate or severe impairment.
• Children and adolescents: no relevant use in RCC and MCL, and not recommended. It should not be used in neuroblastoma, rhabdomyosarcoma or high-grade glioma because of efficacy concerns.

Dose-Dependence

The incidence and severity of adverse events depend on the dose. Patients on the 175 mg weekly starting dose for MCL must be followed closely to decide on dose reductions or delays.

Hypersensitivity and Infusion Reactions

• Reactions such as flushing, chest pain, dyspnoea, hypotension, apnoea, loss of consciousness, hypersensitivity and anaphylaxis can occur very early in the first infusion but also with later ones. Patients should be monitored early in each infusion, with supportive care available. The infusion is interrupted in all patients with severe reactions and appropriate treatment given; benefit and risk are reassessed before continuing after a severe or life-threatening reaction.
• If a reaction occurs despite premedication, the infusion must be stopped and the patient observed for at least 30 to 60 minutes. At the physician’s discretion it may then be restarted after an H1 antagonist (diphenhydramine or similar) and an H2 antagonist (for example intravenous famotidine 20 mg) about 30 minutes beforehand. Corticosteroids may be considered, though their efficacy here is not established. The infusion is then resumed more slowly (up to 60 minutes) and finished within six hours of first adding temsirolimus to the sodium chloride solution.
• Use with caution in patients with a known hypersensitivity to the antihistamine or who cannot receive it.

Hyperglycaemia

Blood glucose may rise in diabetic and non-diabetic patients (hyperglycaemia was reported in 26% of RCC and 11% of MCL trial patients), and insulin or oral glucose-lowering treatment may need to be started or increased. Patients should report excessive thirst or any increase in the volume or frequency of urination.

Infections

Patients may be immunosuppressed and should be watched for infections, including opportunistic infections. Infections were substantially more frequent with 175 mg weekly in MCL. Pneumocystis jirovecii pneumonia (PCP), some fatal, has been reported, often in patients also on corticosteroids or other immunosuppressants; PCP prophylaxis should be considered when these are needed.

Interstitial Lung Disease

Non-specific interstitial pneumonitis, including fatal cases, has occurred. A baseline chest CT scan or radiograph is recommended before starting, and patients should report new or worsening respiratory symptoms promptly. Temsirolimus may be withheld until symptoms and radiographic findings improve; opportunistic infections such as PCP should be considered, and corticosteroids and/or antibiotics may be used.

Lipids, Wound Healing and Malignancy

• Hyperlipaemia: serum triglycerides and cholesterol rise; they should be tested before and during treatment, and lipid-lowering treatment may be needed. The association may predispose to myocardial infarction.
• Wound healing: abnormal wound healing has been associated with temsirolimus, so caution is needed in the peri-surgical period.
• Malignancy: immunosuppression may lead to lymphoma and other malignancies, particularly of the skin. Sunlight and UV exposure should be limited with protective clothing and high-factor sunscreen.

Blood Counts, Bleeding, Kidney and Liver

• Blood counts: grade 3 and 4 thrombocytopenia and neutropenia were seen in MCL. A complete blood count is recommended before starting and periodically afterwards. Thrombocytopenia increases bleeding risk (including epistaxis), and patients with baseline neutropenia may develop febrile neutropenia.
• Intracerebral bleeding: patients with CNS tumours (primary or metastatic) or on anticoagulants may be at increased risk of intracerebral bleeding, including fatal cases.
• Renal failure: kidney elimination is negligible and the drug has not been studied in haemodialysis, but renal failure (including fatal outcomes) has occurred in patients with advanced RCC or pre-existing renal insufficiency.
• Liver: AST and bilirubin should be measured before starting and periodically. Temsirolimus is cleared mainly by the liver, and more fatal events occurred in patients with moderate and severe hepatic impairment, though a causal link cannot be excluded.

Vaccination

Immunosuppressants may affect vaccine responses, so vaccination during treatment may be less effective. Live vaccines should be avoided; examples are measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and the TY21a typhoid vaccine.

Excipients: Ethanol and Propylene Glycol

• Ethanol: after first dilution the mixture contains 35% volume ethanol, up to 0.693 g per 25 mg dose; the 175 mg MCL dose may bring up to 4.85 g (equal to about 122 mL of beer or 49 mL of wine). For an adult weighing 70 kg this would raise blood alcohol by about 11.5 mg/100 mL. It is not likely to have an effect in adults and adolescents, but may cause somnolence in neonates and young children. Care is needed in pregnant or breast-feeding women, people with alcoholism, and high-risk groups such as patients with liver disease or epilepsy. It may alter the effects of other medicines and may impair the ability to drive or use machines.
• Propylene glycol: the 175 mg dose in a 70 kg adult gives about 50.33 mg/kg/day. Medical monitoring, including the osmolar and/or anion gap, is needed in patients with impaired renal or hepatic function who receive 50 mg/kg/day or more. Prolonged use, or use with other alcohol dehydrogenase substrates such as ethanol, increases the risk of accumulation and toxicity.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data in pregnant women. In rats and rabbits temsirolimus caused embryo-foetal toxicity (death, reduced foetal weight with delayed ossification), and in rabbits omphalocele. It must not be used in pregnancy unless the benefit to the mother justifies the risk to the embryo. The ethanol content should also be taken into account. Propylene glycol may reach the foetus, and giving 50 mg/kg/day or more to pregnant women should be considered only case by case.
• Contraception: 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 during treatment.
• Breastfeeding: it is unknown whether temsirolimus passes into human milk, but sirolimus passes into the milk of rats. Breast-feeding should be stopped during therapy.
• Fertility: in male rats, decreased fertility and partly reversible reductions in sperm counts were reported.

Effect on Driving

Temsirolimus has no or negligible influence on the ability to drive and use machines. With the 175 mg MCL dose, the ethanol content may impair this ability.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vials in the outer carton to protect from light. Torisel is therefore supplied and held under cold-chain conditions until use. After dilution, follow the in-use times given under Shelf Life.

• Unopened vial: 4 years.
• After first dilution of the concentrate with 1.8 mL of the supplied solvent: 24 hours when stored below 25 °C and protected from light.
• After further dilution with sodium chloride 9 mg/mL (0.9%) solution for injection: 6 hours when stored below 25 °C and protected from light.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), and given under the supervision of a physician experienced in antineoplastic medicinal products. Torisel is infused in hospital, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.