Overview
11 DESCRIPTION Temsirolimus, an inhibitor of mTOR, is an antineoplastic agent. Temsirolimus is a white to off-white powder with a molecular formula of C 56 H 87 NO 16 and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of pH.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.
Indications
- 1 INDICATIONS AND USAGE Temsirolimus injection is indicated for the treatment of advanced renal cell carcinoma. Temsirolimus injection is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma. ( 1 )
Common Doses
- 25 mg
- 250 mL
- 50 mg
- 5 mg
Dosage
2 DOSAGE AND ADMINISTRATION The recommended dose of Temsirolimus injection is 25 mg administered as an intravenous infusion over a 30-60 minute period once a week. Treat until disease progression or unacceptable toxicity. ( 2.1 ) Antihistamine pre-treatment is recommended. ( 2.2 ) Dose reduction is required in patients with mild hepatic impairment. ( 2.4 ) 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. ( 2.5 ) 2.
Contraindications
- 4 CONTRAINDICATIONS Temsirolimus injection is contraindicated in patients with bilirubin >1.5×ULN [see Warnings and Precautions ( 5.2 )]. Temsirolimus injection is contraindicated in patients with bilirubin > 1.5×ULN. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The following serious adverse reactions have been associated with Temsirolimus injection in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions ( 5 )] . Hypersensitivity/Infusion Reactions [see Warnings and Precautions ( 5.1 )] Hepatic Impairment [see Warnings and Precautions ( 5.2 )] Hyperglycemia/Glucose Intolerance [see Warnings and Precautions ( 5.3 )] Infections [see Warnings and Precautions ( 5.4 )] Interstitial Lung Disease [see Warnings and Precautions ( 5.
Interactions
- 7 DRUG INTERACTIONS Strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect concentrations of the primary metabolite of Temsirolimus injection. If alternatives cannot be used, dose modifications of Temsirolimus injection are recommended. ( 7.1 , 7.2 , 7.3 ) 7.1 Agents Inducing CYP3A Metabolism Co-administration of Temsirolimus injection with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus C max (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus C max by 65% and...