Torisel

Temsirolimus Instructions
Common name: Temsirolimus
Trade name: Torisel
All names: Temsirolimus, Temsirolimus, Torisel, Temsirolimus, Temsirolimus, Torisel

Indications:
Suitable for the treatment of advanced renal cell carcinoma.

Usage and dosage:
(1) Recommended dose:
The recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg, infused over 30-60 minutes, once a week. Continue treatment until disease progression or intolerance.
(2) Pre-medication:
Preventive intravenous infusion of 25-30mg diphenhydramine (or other antihistamines) is required before each dose, lasting about 30 minutes.
(3) Dose adjustment:
Suspend administration when absolute neutrophil count (ANC) < 1,000/mm3, platelet count < 75,000/mm3, or NCICTCAE grade 3 or greater adverse reactions. Once toxicity has resolved to Grade 2 or less, Torisel administration can be resumed, adjusting the dose in 5 mg/week increments and ensuring that the dose does not fall below 15 mg/week.

Adverse reactions:
Serious adverse reactions include: hypersensitivity reactions, hyperglycemia/glucose intolerance, liver damage, infection, interstitial lung disease, hyperlipidemia, intestinal perforation, renal failure, intracranial hemorrhage, etc.
Most common (≥ 30%)
Adverse reactions include: rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥ 30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

Contraindications:
TORISEL is contraindicated in patients with bilirubin >1.5×ULN.

Notes:
(1) Hypersensitivity reaction: Symptoms of hypersensitivity reaction have been observed in patients receiving TORISEL treatment, including but not limited to: allergic reaction, dyspnea, flushing and chest pain. TORISEL should be used with caution in patients with a hypersensitivity reaction to sirolimus esters or its metabolites (including sirolimus), polysorbate 80, or to any component of TORISEL. Patients should be given an H1 antihistamine before starting the intravenous sirolimus lipid infusion. TORISEL should be used with caution in patients who are hypersensitive to antihistamines or who are unable to receive an antihistamine for other medical reasons. If a patient develops a hypersensitivity reaction during an infusion of TORISEL, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). Treatment can be resumed at the doctor's discretion. If patients have not been given H1-receptor antagonists or H2-receptor antagonists before, they must be re-administered 30 minutes before Torisel infusion. And it took 60 minutes to complete the Torisel infusion.
(2) Liver damage: Patients with mild liver damage must use it with caution. It is contraindicated in patients with bilirubin >1.5×ULN. If TORISEL must be administered in patients with mild hepatic impairment (bilirubin >1–1.5 x ULN or AST >ULN and bilirubin ≤ ULN), reduce the TORISEL dose to 15 mg/week.
(3) Hyperglycemia/glucose intolerance: The use of TORISEL is likely to cause an increase in serum glucose. Serum glucose should be tested before and during treatment with TORISEL. Report to your doctor if you experience severe thirst, frequent urination, or increased urine output.
(4) Infection: The use of TORISEL may cause immunosuppression. Patients should be carefully observed for the occurrence of infection.
(5) Interstitial lung disease: A condition of interstitial lung disease that sometimes results in death in patients receiving TORISEL. Some patients have no symptoms or mild symptoms on CT scan and chest X-ray. Other symptoms include dyspnea, cough, hypoxia and fever. Some patients will need to suspend dosing and receive corticosteroids or antibiotics, and some will need to continue treatment without other intervention. Patients are advised to promptly report the onset or worsening of respiratory symptoms.
(6) Hyperlipidemia: The use of TORISEL is likely to cause an increase in serum triglycerides and cholesterol. Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL.
(7) Intestinal perforation: Cases of fatal intestinal perforation have occurred in patients receiving TORISEL. These patients have fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, or acute abdomen. Patients should be advised to report any new abdominal pain or bloody stools or worsening symptoms.
(8) Renal failure: In some cases of rapid disease progression and acute renal failure, it is not yet clear whether it is related to Torisel treatment, and some patients in these cases do not respond to dialysis treatment.
(9) Wound healing complications: The use of TORISEL has been associated with abnormal wound healing. Therefore, use of TORISEL during surgery should be treated with caution.
(10) Intracranial hemorrhage: Patients with central nervous system tumors (primary or metastatic central nervous system tumors) and patients receiving anticoagulant therapy may be at increased risk of intracranial hemorrhage (which may be fatal) when receiving Torisel treatment.
(11) Concomitant administration with CYP3A inducers or inhibitors: drugs that induce CYP3A metabolism: strong CYP3A4/5 inducers, such as dexamethasone [dexamethasone], carbamazepine [carbamazepine] , phenytoin, phenobarbital, rifampin, rifabutin, and rifampacin may reduce exposure to the active metabolite sirolimus. If additional treatment cannot be given, dose adjustment should be considered. It is not known whether St. John's wort can reduce Torisel blood levels. Therefore, patients should avoid taking St. John's wort at the same time. Drugs that inhibit CYP3A metabolism: Strong CYP3A4 inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If additional treatment cannot be given, dose adjustment should be considered.
(12) Concomitant use of TORISEL with sunitinib: Concomitant use of TORISEL with sunitinib resulted in dose-limiting toxicities (Grade 3/4 erythematous papular rash, and gout/cellulitis requiring hospitalization). In a phase 1 study at doses of TORISEL 15 mg IV weekly and sunitinib 25 mg PO daily (on days 1-28, followed by 2 weeks off), dose-limiting toxicities were observed in 2 of 3 patients.
(13) Vaccination: Vaccination and close contact with vaccinated persons should be avoided during treatment with TORISEL. Examples of live vaccines are: nasal drop influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, chickenpox and TY21a typhoid vaccine.
(14) Pregnancy: It is recommended that women of reproductive potential must take effective contraceptive measures during treatment and for 3 months after completing treatment. Men must use effective contraception during treatment and for 3 months after completing treatment.
(15) Surveillance laboratory tests In a randomized level 3 clinical trial, patients underwent a complete blood count once a week and a blood test every two weeks. Laboratory monitoring of Torisel-treated patients will be performed at physician discretion.
(16) Medication for the elderly: Based on the results of a phase III clinical trial, elderly patients may be more prone to adverse reactions such as diarrhea, edema, and pneumonia.

Storage:
The medicine box should be stored in a refrigerator at 2℃8°C (36°46°F) and protected from light.

Mechanism of action:
Temsirolimus is an inhibitor of mTOR (target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR, which controls cell division. Inhibition of mTOR activity results in a G1 growth arrest in treated tumor cells. When mTOR is inhibited, its ability to phosphorylate p70s6k and S6 ribosomal proteins downstream of mTOR in the PI3 kinase/AKT pathway is blocked. In in vitro studies using renal cell carcinoma cell lines, sirolimus lipids inhibited the activity of mTOR and resulted in reduced levels of hypoxia-inducible factors HIF-1 and HIF-2, and vascular endothelial growth factor.

Efficacy and safety:
In vitro studies have found that this product can inhibit mTOR kinase and lead to a decrease in the levels of certain vascular growth factors (such as vascular endothelial growth factor), thereby preventing the development of new blood vessels. It is currently the only drug that can significantly prolong the survival of patients. A total of 626 patients with renal cell carcinoma from 209 regions in 26 countries were enrolled in the Phase IIl clinical trial of this drug, and were randomly assigned to the interferon treatment group (3×106-18×106U, 3 times a week, SC), the Torisel treatment group (25mg, once a week, iv), and the Torisel + interferon group (Torisel 15mg, once a week, iv, interferon 6×106U, 3 times a week, SC). The results showed that Torisel significantly prolonged the survival rate of patients by 49% compared with interferon (10.9 vs. 8.7.3 months, P = 0.0078); in terms of secondary evaluation indicators, Torisel significantly prolonged the progression-free (disease does not worsen) survival of patients compared with interferon alone (5.5 vs. 3.1 months, P = 0.0001).