Temsirolimus

TORISEL is indicated for the treatment of advanced renal cell carcinoma. TORISEL ® is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma.

Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.

• The recommended dose of TORISEL is 25 mg administered as an intravenous infusion over a 30–60 minute period once a week. Treat until disease progression or unacceptable toxicity. • Antihistamine pre-treatment is recommended. • Dose reduction is required in patients with mild hepatic impairment. • TORISEL (temsirolimus) injection vial contents must first be diluted with the enclosed diluent before diluting the resultant solution with 250 mL of 0.9% Sodium Chloride Injection.

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

• Hypersensitivity/Infusion Reactions (including some life-threatening and rare fatal reactions) can occur early in the first infusion of TORISEL. Patients should be monitored throughout the infusion. • To treat hypersensitivity reactions, stop TORISEL and treat with an antihistamine. TORISEL may be restarted at physician discretion at a slower rate. • Hepatic Impairment: Use caution when treating patients with mild hepatic impairment and reduce dose. • Hyperglycemia and hyperlipidemia are likely and may require treatment. Monitor glucose and lipid profiles. • Infections may result from immunosuppression. • Monitor for symptoms or radiographic changes of interstitial lung disease (ILD). If ILD is suspected, discontinue TORISEL, and consider use of corticosteroids and/or antibiotics. • Bowel perforation may occur.

The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label. • Hypersensitivity/Infusion Reactions • Hepatic Impairment • Hyperglycemia/Glucose Intolerance • Infections • Interstitial Lung Disease • Hyperlipidemia • Bowel Perforation • Renal Failure • Wound Healing Complications • Intracerebral Hemorrhage The most common (≥30%) adverse reactions observed with TORISEL are 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.

Strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect concentrations of the primary metabolite of TORISEL. If alternatives cannot be used, dose modifications of TORISEL are recommended.

Each kit is supplied in a single carton containing one single-use vial of 25 mg/mL of temsirolimus and one DILUENT vial which includes a deliverable volume of 1.8 mL, and must be stored at 2º–8º C (36º–46º F). Protect from light.