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Drug: Temsirolimus - Torisel™

Usual Diluents

Dilution Data

DILUTION SUMMARY

[Amount of drug] [Infusion volume] [Infusion rate]

[Prescribed dose ] [250 ml NS] [ 30 - 60 minutes]

-Reconstitute with supplied diluent (see below).
-Must use non-PVC bags and tubing.
-An in-line polyethersulfone filter with a pore size < 5 microns is recommended for administration.
-Mix the admixture by inversion of the bag or bottle. Avoid excessive shaking as this may cause foaming.

Instructions for Preparation and Administration: TORISEL must be stored under refrigeration at 2°-8°C (36°-46°F) and protected from light. During handling and preparation of admixtures, TORISEL 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. NO PVC: 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 TORISEL dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

----------------------
Dilution:
----------------------
In preparing the TORISEL administration solution, follow this two-step dilution process in an aseptic manner.
Step 1:
Inject 1.8 mL of DILUENT for TORISEL® into the vial of TORISEL (temsirolimus) injection (25 mg/ml). The TORISEL (temsirolimus) vial contains an overfill of 0.2 mL (30 mg/1.2 mL). Due to the intentional overfill in the TORISEL injection vial, the drug concentration of the resulting solution will be 10 mg/mL. A total volume of 3 mL will be obtained including the overfill. Mix well by inversion of the vial. Allow sufficient time for air bubbles to subside. This 10 mg/mL drug solution/diluent mixture must be further diluted as described in Step 2 below. The solution is clear to slightly turbid, colorless to yellow, and free from visual particulates. The 10 mg/mL drug solution/diluent mixture is stable for up to 24 hours at controlled room temperature.

Step 2:
Withdraw the required amount of temsirolimus from the 10 mg/mL drug solution/diluent mixture prepared in Step 1. Inject rapidly into a 250 mL container (glass, polyolefin, or polyethylene) of 0.9% sodium chloride injection. Mix the admixture by inversion of the bag or bottle. Avoid excessive shaking as this may cause foaming.
----------------------
Administration:
----------------------

The sodium chloride injection container should be composed of non-DEHP containing materials, such as glass, polyolefin or polyethylene, and the administration set should consist of non-DEHP tubing to avoid extraction of di-(2-ethylhexyl) phthalate (DEHP). TORISEL contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from PVC.
An in line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration.
The final diluted solution of TORISEL is intravenously infused over a 30-60 minute period once a week. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the drug.
Administration of the final diluted infusion solution should be completed within six hours from the time that the drug solution/diluent mixture is added to the sodium chloride injection

Stability / Miscellaneous

WARNINGS/PRECAUTIONS - See package insert.	CLINICAL PHARMACOLOGY	INDICATIONS
CONTRAINDICATIONS	DOSAGE AND ADMINISTRATION	RECONSTITUTION / DILUTION
	HOW SUPPLIED
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CLINICAL PHARMACOLOGY

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.

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

2. DOSAGE AND ADMINISTRATION

2.1 Advanced Renal Cell Carcinoma
The recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg infused 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 TORISEL [see PACKAGE INSERT for Hypersensitivity Reactions (5.1)].

2.3 Dosage Interruption/Adjustment
TORISEL should be held for absolute neutrophil count (ANC) < 1,000/mm³, platelet count < 75,000/mm³, or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, TORISEL may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week.

2.4 Dose Modification Guidelines
Hepatic Impairment: Use caution when treating patients with hepatic impairment. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin

ULN), reduce the dose of TORISEL to 15 mg/week. TORISEL is contraindicated in patients with bilirubin >1.5 x ULN [ see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ) and see PACKAGE INSERT for 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 TORISEL dose reduction to 12.5 mg/week should be considered. This dose of TORISEL 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 TORISEL dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor [see see PACKAGE INSERT for 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, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a TORISEL dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of TORISEL 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 see PACKAGE INSERT for Drug Interactions (7.1)].

2.5 Instructions for Preparation and Administration
TORISEL must be stored under refrigeration at 2°-8°C (36°-46°F) and protected from light. During handling and preparation of admixtures, TORISEL 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 TORISEL dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

----------------------
Dilution:
----------------------
In preparing the TORISEL administration solution, follow this two-step dilution process in an aseptic manner.

Step 1:
Inject 1.8 mL of DILUENT for TORISEL® into the vial of TORISEL (temsirolimus) injection (25 mg/ml). The TORISEL (temsirolimus) vial contains an overfill of 0.2 mL (30 mg/1.2 mL). Due to the intentional overfill in the TORISEL injection vial, the drug concentration of the resulting solution will be 10 mg/mL. A total volume of 3 mL will be obtained including the overfill. Mix well by inversion of the vial. Allow sufficient time for air bubbles to subside. This 10 mg/mL drug solution/diluent mixture must be further diluted as described in Step 2 below.

The solution is clear to slightly turbid, colorless to yellow, and free from visual particulates. The 10 mg/mL drug solution/diluent mixture is stable for up to 24 hours at controlled room temperature.

Step 2:
Withdraw the required amount of temsirolimus from the 10 mg/mL drug solution/diluent mixture prepared in Step 1. Inject rapidly into a 250 mL container (glass, polyolefin, or polyethylene) of 0.9% sodium chloride injection. Mix the admixture by inversion of the bag or bottle. Avoid excessive shaking as this may cause foaming.
----------------------
Administration:
----------------------

The sodium chloride injection container should be composed of non-DEHP containing materials, such as glass, polyolefin or polyethylene, and the administration set should consist of non-DEHP tubing to avoid extraction of di-(2-ethylhexyl) phthalate (DEHP). TORISEL contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl) phthalate (DEHP) extraction from PVC.
An in line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration.
The final diluted solution of TORISEL is intravenously infused over a 30-60 minute period once a week. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the drug.
Administration of the final diluted infusion solution should be completed within six hours from the time that the drug solution/diluent mixture is added to the sodium chloride injection

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Compatibilities and Incompatibilities
-----------------------------------------------------------
Undiluted TORISEL injection should not be added directly to aqueous infusion solutions. Direct addition of TORISEL injection to aqueous solutions will result in precipitation of drug. Always combine TORISEL injection with DILUENT for TORISEL® before adding to infusion solutions. It is recommended that TORISEL be administered in 0.9% sodium chloride injection after combining with diluent. The stability of TORISEL in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of TORISEL in 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.

3. DOSAGE FORMS AND STRENGTHS
TORISEL (temsirolimus) is supplied as a kit consisting of the following:

TORISEL (temsirolimus) injection (25 mg/ml). The TORISEL vial includes an overfill of 0.2 mL.

DILUENT for TORISEL®. The DILUENT vial includes a deliverable volume of 1.8 mL.

4. CONTRAINDICATIONS
TORISEL is contraindicated in patients with bilirubin >1.5 x ULN [ see Warnings and Precautions ( 5.2 )].

HOW SUPPLIED/STORAGE AND HANDLING
NDC 0008-1179-01 TORISEL® (temsirolimus) injection, 25 mg/mL.

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 2°-8°C (36° 46°F). Protect from light

Wyeth Pharmaceuticals Inc.
Manufactured for: Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101

TORISEL® (temsirolimus) injection is manufactured by: Pierre Fabre Medicament Production, Aquitaine Pharm International, Avenue du Bearn, F64320 Idron, France

DILUENT for TORISEL® is manufactured by: Ben Venue Laboratories, Inc., Bedford, Ohio 44146-0568

Reference(s)

1) [PACKAGE INSERT DATA] : TORISEL (temsirolimus) kit. [Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc.] Philadelphia, PA 19101. Rev 07/10.