Temsirolimus

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 ) 2.1 Advanced Renal Cell Carcinoma The recommended dose of temsirolimus injection for advanced renal cell carcinoma is 25 mg administered as an intravenous infusion over a 30-60 minute period once a week. Treatment should continue until disease progression or unacceptable toxicity occurs. 2.2 Premedication Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus injection [see Warnings and Precautions ( 5.1 )] . 2.3 Dosage Interruption/Adjustment Temsirolimus injection should be held for absolute neutrophil count (ANC) 1 – 1.5xULN or AST >ULN but bilirubin ≤ULN), reduce the dose of temsirolimus injection to 15 mg/week. Temsirolimus injection is contraindicated in patients with bilirubin >1.5xULN [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.7 )] . Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a temsirolimus injection dose reduction to 12.5 mg/week should be considered. This dose of temsirolimus injection is predicted to adjust the AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the temsirolimus injection dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor [see Warnings and Precautions ( 5.12 ) and Drug Interactions ( 7.2 )] . Concomitant Strong CYP3A4 Inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a temsirolimus injection dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of temsirolimus injection is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Warnings and Precautions ( 5.12 ) and Drug Interactions ( 7.1 )] . 2.5 Instructions for Preparation Temsirolimus injection is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . Temsirolimus injection must be stored under refrigeration at 2° to 8°C (36° to 46°F) and protected from light. During handling and preparation of admixtures, temsirolimus injection should be protected from excessive room light and sunlight. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final temsirolimus injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Temsirolimus injection 25 mg/mL must be diluted with the supplied diluent before further dilution in 0.9% Sodium Chloride Injection, USP. Please note that both the temsirolimus injection and diluent vials contain an overfill to ensure the recommended volume can be withdrawn. Follow this two-step dilution process in an aseptic manner. Step 1: DILUTION OF TEMSIROLIMUS INJECTION 25 MG/ML WITH SUPPLIED DILUENT Each vial of temsirolimus injection must first be mixed with 1.8 mL of the enclosed diluent. The resultant solution contains 30 mg/3 mL (10 mg/mL). Mix well by inversion of the vial. Allow sufficient time for the air bubbles to subside. The solution should be clear to slightly turbid, colorless to light-yellow solution, essentially free from visual particulates. The concentrate-diluent mixture is stable below 25ºC for up to 24 hours. Step 2: DILUTION OF CONCENTRATE-DILUENT MIXTURE WITH 0.9% SODIUM CHLORIDE INJECTION, USP Withdraw precisely the required amount of concentrate-diluent mixture containing temsirolimus 10 mg/mL as prepared in Step 1 from the vial (i.e., 2.5 mL for a temsirolimus dose of 25 mg) and further dilute into an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. Mix by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming. The resulting solution should be inspected visually for particulate matter and discoloration prior to administration. The admixture of temsirolimus injection in 0.9% Sodium Chloride Injection, USP should be protected from excessive room light and sunlight. 2.6 Administration Administration of the final diluted solution should be completed within six hours from the time that temsirolimus injection is first added to 0.9% Sodium Chloride Injection, USP. Temsirolimus injection is administered as an intravenous infusion over a 30-to 60-minute period once weekly. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the product. Appropriate administration materials should be composed of glass, polyolefin, or polyethylene to avoid excessive loss of product and diethylhexylpthalate (DEHP) extraction. The administration materials should consist of non-DEHP, non-polyvinylchloride (PVC) tubing with appropriate filter. In the case when a PVC administration set has to be used, it should not contain DEHP. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused. If the administration set available does not have an in-line filter incorporated, a polyethersulfone filter should be added at the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used, ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended. Temsirolimus injection, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This should be considered during the preparation and administration of temsirolimus injection, including storage time elapsed when in direct contact with PVC following constitution. Compatibilities and Incompatibilities Undiluted temsirolimus injection should not be added directly to aqueous infusion solutions. Direct addition of temsirolimus injection to aqueous solutions will result in precipitation of drug. Always combine temsirolimus injection with DILUENT for temsirolimus injection before adding to infusion solutions. It is recommended that temsirolimus injection be administered in 0.9% Sodium Chloride Injection after combining with diluent. The stability of temsirolimus injection in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of temsirolimus injection in 0.9% Sodium Chloride Injection has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution pH should be avoided.

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1 INDICATIONS AND USAGE Temsirolimus injection is indicated for the treatment of advanced renal cell carcinoma.